Ion pair catalysis of tungstate and molybdate

ABSTRACT

D The present invention relates to ion pair catalysts (I) comprising the cationic bisguanidinium ligand (A) and diperoxomolybdate anion (B). The present invention also relates to ion pair catalysts (III) comprising the cationic bisguanidinium ligand (C) and peroxotungstate anion (D). It further relates to the use of the said catalysts in the manufacture of enantiomerically enriched sulfoxides.

FIELD OF INVENTION

The current application relates to compounds for the preparation ofenantiopure chiral sulfoxides. The application also relates to methodsfor the preparation of the same.

BACKGROUND

The listing or discussion of an apparently prior-published document inthis specification should not necessarily be taken as an acknowledgementthat the document is part of the state of the art or is common generalknowledge.

Sodium tungstate-catalyzed epoxidation of α,β-unsaturated acids usingH₂O₂ in water was first demonstrated by Payne in 1959 and was followedup by Sharpless in 1985 (G. B. Payne, et al., J. Org. Chem. 1959, 24,54; K. S. Kirshenbaum, et al., J. Org. Chem. 1985, 50, 1979). Tungstatesare known to be polymeric in aqueous solutions and the distribution ofthe polyoxotungstate species is dependent on pH and concentration.Peroxotungstate complexes are known to be the catalytic species in thesereactions (K. A. Jørgensen, Chem. Rev. 1989, 89, 431; M. H. Dickman, etal., Chem. Rev. 1994, 94, 569; N. Mizuno, et al., Coordin. Chem. Rev.2005, 249, 1944). Investigation by Venturello into the role of phosphatein phase transfer tungstate oxidation reactions, resulted in theisolation and identification of the heteropolyperoxotungstate,[PO₄{WO(O₂)₂}₄]³⁻ (C. Venturello, et al., J. Org. Chem. 1983, 48, 3831;C. Venturello, et al., J. Mol. Catal. 1985, 32, 107). Thisperoxotungstate species was also postulated to be the catalyticallyactive species for the H₃PW₁₂O₄₀/H₂O₂(Keggin's reagent) oxidation systemdeveloped by Ishii (Y. Ishii, et al., J. Org. Chem. 1988, 53, 3587; A.J. Bailey, et al., J. Chem. Soc., Dalton. Trans. 1995, 1833; D. C.Duncan, et al., J. Am. Chem. Soc. 1995, 117, 681) Subsequently, Noyorideveloped an efficient catalyst suitable on a practical scale with highturnover number. It was found that (aminomethyl)phosphonic acid orphenylphosphonic acid was effective in accelerating the reaction. It wasproposed that a 1:1 complex between phosphonic acid andmonoperoxotungstate is the active catalyst (R. Noyori, et al., Chem.Commun. 2003, 1977). Using this methodology, they furnished olefinepoxidation (K. Sato, et al., J. Org. Chem. 1996, 61, 8310) andsulfoxidation (K. Sato, et al., Tetrahedron 2001, 57, 2469) in highchemoselectivities.

Molybdenum-based systems have been extensively applied in the field ofinorganic, organic and biological chemistry (J. Burke & E. P. Carreiro.in Comprehensive Inorganic Chemistry II (Second Edition), 309-382(Elsevier, 2013)). Molybdenum metalloenzymes play an important role inthe metabolism of nitrogen (Yoshiaki Nishibayashi, Inorg. Chem. 54,9234-9247 (2015)), sulfur, and carbon compounds (R. Hille, et al., Chem.Rev. 114, 3963-4038 (2014); Barbara K. Burgess & David J. Lowe, Chem.Rev. 96, 2983-3012 (1996); Günter Schwarz, et al., Nature 460, 839-847(2009)). Over recent years, various molybdenum compounds have beendeveloped and successfully applied in a number of organictransformations. In particular, the properties of the oxomolybdenum (VI)anionic species have been comprehensively investigated and described. Itis worthy of note that the reactions with organic ligands, strong acidsand oxidants allow the formation of numerous ionic complexes ofmolybdenum. A few heteropolymolybdate complexes (Alan J. Bailey, et al.,J. Chem. Soc., Dalton Trans., 1833-1837 (1995); N. Melanie Gresley, etal, J. Mol. Catal. A: Chem. 117, 185-198 (1997); Karl-Heinz Tytko &Dieter Gras, (Springer Berlin Heidelberg, 1988) involving nitrate,fluoride, chloride and phosphate groups (Li Mingqiang & Jian Xigao,Bull. Chem. Soc. Jpn. 78, 1575-1579 (2005)) have been investigated toafford more structural and catalytic diversity.

Molybdate ions can act as catalysts for the activation of H₂O₂ byforming monomeric or polymeric peroxomolybdates, which are highlydependent on pH value of the solution and the quantity of H₂O₂(ValeriaConte & Barbara Floris, Dalton Trans. 40, 1419-1436 (2011); Michael H.Dickman & Michael T. Pope, Chem. Rev. 94, 569-584 (1994)).

The coordination pattern and fine structure of peroxomolybdate anionsand corresponding counter cations can have a significant impact on theirperformance as oxidizing reagents (Xianying Shi & Junfa Wei, Appl.Organomet. Chem. 21, 172-176 (2007)). Recently, the coordinationchemistry of anionic peroxomolybdate species with different organicligands such as citric and malic acids (Zhao-Hui Zhou, et al., DaltonTrans., 1393-1399 (2004)), amino acids (Katarzyna Serdiuk, et al.,Transition Met. Chem. (London) 26, 538-543) and oxalic acid (Andrew C.Dengel, et al., J. Chem. Soc., Dalton Trans., 991-995 (1987); RajanDeepan Chakravarthy, et al., Green Chem. 16, 2190-2196 (2014)) have beensystemically investigated. However, the protocol for preparation ofperoxomolybdenum complex with a sulfate ligand is limited (Chang G. Kim,et al., Inorg. Chem. 32, 2232-2233 (1993); Masato Hashimoto, et al., J.Coord. Chem. 37, 349-359 (1996); Fabian Taube, et al., J. Chem. Soc.,Dalton Trans., 1002-1008 (2002); Dao-Li Deng, et al., WO2006094577A1(2006)) only one example using such a system for the catalysis of olefinepoxidation reaction has been reported so far (Laurent Salles, et al.,Bull. Soc. Chim. Fr. 133, 319-328 (1996)).

The preparation of enantiopure chiral sulfoxides is an important fieldbecause new and better methods will enable more convenient access topotential drug molecules (for selected reviews, see: a) I. Fernández, N.Khiar, Chem. Rev. 2003, 103, 3651; b) H. B. Kagan, T. O. Luukas,Transition Metals for Organic Synthesis: Building Blocks and FineChemicals, Second Revised and Enlarged Edition. 2004: 479; c) H. B.Kagan, Wiley-VCH: Weinheim, Germany, 2008; d) G. E. O'Mahony, A. Ford,A. R. Maguire, J. Sulfur Chem. 2013, 34, 301).

Currently, the Kagan oxidation is widely used for asymmetricsulfoxidation (H. B. Kagan, F. Rebiere, Synlett 1990, 11, 643) but thereare emerging methods (F. A. Davis, R. T. Reddy, W. Han, P. J. Carroll,J. Am. Chem. Soc. 1992, 114, 1428; J. Legros, C. Bolm, Angew. Chem. Int.Ed. 2004, 43, 4225; Angew. Chem. 2004, 116, 4321; C. Drago, L. Caggiano,R. F. W. Jackson, Angew. Chem. Int. Ed. 2005, 44, 7221; Angew. Chem.2005, 117, 7387; J. Fujisaki, K. Matsumoto, K. Matsumoto, T. Katsuki, J.Am. Chem. Soc. 2011, 133, 56) to prepare chiral sulfoxides includingsome recent breakthroughs utilizing imidodiphosphoric acid (S. Liao, I.Čorić, Q. Wang, B. List, J. Am. Chem. Soc. 2012, 134, 10765), binucleartitanium chiral complex (S. Bhadra, M. Akakura, H. Yamamoto, J. Am.Chem. Soc. 2015, 137, 15612), or pentanidium (L. Zong, X. Ban, C. W.Kee, C.-H. Tan, Angew. Chem. Int. Ed. 2014, 53, 11849; Angew. Chem.2014, 126, 12043).

There remains a need for new methods of accessing chiral sulfoxides inhigh enantiopurities and for catalysts/catalyst systems that can be usedto accomplish these as current methods may not be able to work withparticular substrate materials of significant interest in the field ofpharmaceuticals and the like.

SUMMARY OF INVENTION

It has been surprisingly found that two complexes are particularly goodat providing an enantioselective sulfoxidation product. These complexesare a molybdate complex and a tungstate complex. When used herein, theterm “complex” may be used interchangeably with “system”.

Molybdate System

Disclosed herein is an in situ generated chiral[bisguanidinium]²⁺[(μ₂-SO₄)Mo₂O₂(μ₂-O₂)₂(O₂)₂]²⁻ complex using a chiralbisguanidinium di-cation paired with inorganic sulfato diperoxomolybdatedianion. This complex has been isolated and its structure has beenunambiguously confirmed by single crystal X-ray diffraction and ⁹⁵Mo NMRtechnique. The precise control on enantioselectivity in sulfideoxidation indicates the highly synergistic interaction of the dicationicbisguanidinium and anionic diperoxomolybdate ion-pair catalyst.

It has been demonstrated below that this complex acts as the realreactive species in the oxidation reaction of organic thioethers by thetransfer of two equivalents of active oxygen atom. Furthermore, thestrategy of using chiral dicationic bisguanidinium for the precisecontrol of the dinuclear oxodiperoxomolybdosulfate dianion species[(μ₂-SO₄) Mo₂O₂(μ₂-O₂)₂(O₂)₂] was successfully applied in the highlystereoselective synthesis of Armodafinil in gram-scale. The successfulidentification of this organic bisguanidinium-inorganic metallic anioncomplex opens up new paradigms for previously inaccessible reactions. Inconclusion, direct enantioselective sulfoxidation using an abundantmolybdate salt and environmentally benign aqueous H₂O₂ has been wellestablished in our present methodology.

Thus, in a first aspect of the invention, there is provided a complex offormula (I), comprising an organic cation (A) and an inorganic anion(B):

wherein:

-   -   each R₁ independently represents C₁₋₃ alkyl-aryl or C₁₋₃        alkyl-Het^(a), which aryl or Het^(a) groups are unsubstituted or        are substituted by from one to five R₃ substituents;        each R₂ independently represents aryl, which group is        unsubstituted or substituted by from one to five R₄        substituents;    -   Het^(a) represents a 4- to 14-membered heterocyclic group        containing one or more heteroatoms selected from O, S and N,        which heterocyclic group may comprise one, two or three rings;    -   each R₃ and R₄ independently represents halo, branched or        unbranched C₁₋₆ alkyl, branched or unbranched C₂₋₆ alkenyl,        branched or unbranched C₂₋₆ alkynyl; C₃₋₆ cycloalkyl, aryl        (which latter five groups are unsubstituted or substituted by        one or more halogen atoms) or OR₅;    -   R₅ represents H, branched or unbranched C₁₋₆ alkyl, branched or        unbranched C₂₋₆ alkenyl, branched or unbranched C₂₋₆ alkynyl,        C₃₋₆ cycloalkyl or aryl (which latter five groups are        unsubstituted or substituted by one or more halogen atoms).

In a second aspect of the invention, there is provided a process ofmanufacturing a sulfoxide, comprising reacting a compound of formula(II):

in the presence of a complex of formula (I), as defined in the firstaspect of the invention (or in any of its embodiments disclosed herein),wherein in the compound of formula (II):

-   -   R₆ represents H, branched or unbranched C₁₋₆ alkyl, branched or        unbranched C₂₋₆ alkenyl, branched or unbranched C₂₋₆ alkynyl,        C₃₋₆ cycloalkyl (which latter three groups are unsubstituted or        substituted by one or more substituents selected from halo, OR₈,        and C(O)R₉), C(O)R₁₀, C(O)OR₁₁ or OR₁₂;    -   R₇ represents CH(R₁₃)(R₁₄), Het^(b) or aryl, which latter two        groups are unsubstituted or substituted by one or more        substituents selected from halo, NO₂, CN, branched or unbranched        C₁₋₆ alkyl (optionally substituted by one or more halo atoms),        C(O)R₁₅ or OR₁₆;    -   R₁₃ and R₁₄ each independently represent H, aryl or Het^(c)        (which latter two groups are unsubstituted or substituted by one        or more substituents selected from halo, branched or unbranched        C₁₋₆ alkyl, C(O)R₁₇ and OR₁₈), provided that at least one of R₁₃        and R₁₄ is not H;    -   R₈, R₁₂, R₁₆ and R₁₈ each independently represent H, C(O)R₁₉ or        a branched or unbranched C₁₋₆ alkyl optionally substituted by        one or more halo atoms;    -   R₉, R₁₀, R₁₅ and R₁₇ each independently represent a branched or        unbranched C₁₋₆ alkyl (optionally substituted by one or more        halo atoms), OR₂₀ or N(R_(20′))(R_(20″));    -   R₁₁ represents a branched or unbranched C₁₋₆ alkyl (optionally        substituted by one or more halo atoms);    -   R₁₉, R₂₀, R_(20′), and R_(20″) each independently represent H or        a branched or unbranched C₁₋₆ alkyl (optionally substituted by        one or more halo atoms);    -   Het^(b) and Het^(c) represent a 4- to 14-membered heteroaromatic        group containing one or more heteroatoms selected from O, S and        N, which heteroaromatic group may comprise one, two or three        rings; and        n represents from 1 to 10.        Tungstate System

Also disclosed herein is an enantioselective tungstate-catalyzedsulfoxidation reaction. High enantioselectivities were achieved for avariety of drug-like heterocyclic sulfides under mild conditions usingstoichiometric quantities of H₂O₂, a cheap and environmentally friendlyoxidant. Synthetic utility was demonstrated through the preparation of(S)-Lansoprazole, a commercial proton-pump inhibitor. The activeion-pair catalyst was identified to be bisguanidiniumdiphosphatobisperoxotungstate using Raman spectroscopy and computationalstudies.

Thus, in a third aspect of the invention, there is provided a complex offormula (III), comprising an organic cation (C) and an inorganic anion(D):

wherein:

-   -   each R₂₁ independently represents C₁₋₃ alkyl-aryl or C₁₋₃        alkyl-Het^(d), which aryl or Het^(d) groups are unsubstituted or        are substituted by from one to five R₂₃ substituents;    -   each R₂₂ independently represents aryl, which group is        unsubstituted or substituted by from one to five R₂₄        substituents;    -   Het^(d) represents a 4- to 14-membered heterocyclic group        containing one or more heteroatoms selected from O, S and N,        which heterocyclic group may comprise one, two or three rings;    -   each R₂₃ and R₂₄ independently represents halo, branched or        unbranched C₁₋₆ alkyl, branched or unbranched C₂₋₆ alkenyl,        branched or unbranched C₂₋₆ alkynyl; C₃₋₆ cycloalkyl, aryl        (which latter five groups are unsubstituted or substituted by        one or more halogen atoms) or OR₂₅;    -   R₂₅ represents H, branched or unbranched C₁₋₆ alkyl, branched or        unbranched C₂₋₆ alkenyl, branched or unbranched C₂₋₆ alkynyl,        C₃₋₆ cycloalkyl or aryl (which latter five groups are        unsubstituted or substituted by one or more halogen atoms).

In a fourth aspect of the invention, there is provided a process ofmanufacturing a sulfoxide, comprising reacting a compound of formula(IV):

in the presence of a catalytic amount of a complex of formula (III), asdefined in the third aspect of the invention (or in any of itsembodiments disclosed herein), and at least one molar equivalent of anoxidising agent relative to the compound of formula (IV), wherein in thecompound of formula (IV):

-   -   R₂₆ represents H, branched or unbranched C₁₋₆ alkyl, branched or        unbranched C₂₋₆ alkenyl, branched or unbranched C₂₋₆ alkynyl,        C₃₋₆ cycloalkyl, aryl, Het^(e) (which latter five groups are        unsubstituted or substituted by one or more substituents        selected from halo, NO₂, CN, C₁₋₆ alkyl (optionally substituted        by one or more halo atoms), and OR₂₈), OR₂₉, CN, or C(O)OR₃₀;    -   R₂₇ represents Het^(f) or aryl, which groups are unsubstituted        or substituted by one or more substituents selected from halo,        NO₂, CN, branched or unbranched C₁₋₆ alkyl (optionally        substituted by one or more halo atoms), or OR₃₁;    -   R₂₈, R₂₉ and R₃₁ each independently represent H, C(O)R₃₂ or a        branched or unbranched C₁₋₆ alkyl optionally substituted by one        or more halo atoms;    -   R₃₀ and R₃₂ each independently represent H or a branched or        unbranched C₁₋₆ alkyl optionally substituted by one or more halo        atoms;    -   each Het^(e) independently represents a 4- to 14-membered        heterocyclic group containing one or more heteroatoms selected        from O, S and N, which heterocyclic group may comprise one, two        or three rings; and    -   Het^(f) represents a 4- to 14-membered heteroaromatic group        containing one or more heteroatoms selected from O, S and N,        which heteroaromatic group may comprise one, two or three rings;        and        n represents from 1 to 10.

DRAWINGS

Certain embodiments of the present disclosure are described more fullyhereinafter with reference to the accompanying drawings.

FIG. 1A depicts an experimental Raman spectrum and vibration diagram ofthe active species as provided by Example 7. Raman setting: 2 mW, 532laser power, 30 seconds; FIG. 1B provides a table comparing theexperimental and calculated vibrational frequencies of variousbond/bonds from the Raman spectrum.

FIG. 2 provides a representation of an ion-pair BG1-P2W generated fromcomputational studies using ONIOM optimization, where Oc represents aperoxo-oxygen that may be a possible reaction site;

FIG. 3 provides a schematic illustration of a possible mechanism of theformation and re-generation of ion-pair BG1-P2W from silver tungstate inthe presence of chiral dicationic bisguanidinium;

FIG. 4 provides a molecular structure of ion-pair BG1-P2W and its use inthe asymmetric sulfoxidation of heterocyclic sulfides;

FIG. 5 depicts molecular structures of various chiral bisguanidiniumderivatives;

FIG. 6A depicts a ORTEP diagram showing X-ray crystal structure of theanionic part of complex (R,R)-1c; FIG. 6B depicts a solid-statestructure of complex (R,R)-1c with ellipsoids (drawn using Mercury)shown at the 50% probability level. DMF and Et₂O molecules, and H-atomshave been omitted for clarity;

FIG. 7 depicts ⁹⁵Mo NMR spectra of A) a tetrabutylammonium analogue[Bu₄N]₂[(μ₂-SO₄){Mo₂O₂(μ₂-O₂)₂(O₂)₂}] and B) complex (R,R)-1c[Bisguanidinium][(μ₂-SO₄){Mo₂O₂(μ₂-O₂)₂(O₂)₂}];

FIG. 8A depicts an ORTEP diagram showing X-ray crystal structure ofcomplex (R,R)-1c (top) and FIG. 8B depicts its constituent cationic andanionic parts;

FIGS. 9A-E depict ORTEP diagrams showing X-ray crystal structure ofproducts (S)-2′a, (S)-2′b, (S)-2′c, (S)-2′q and (S)-2′m respectively;

FIGS. 10A-C depict ORTEP diagrams showing X-ray crystal structure ofproducts (R)-8f, (S)-10f and (R)-13 respectively;

FIG. 11 depicts possible coordination configurations of peroxotungstatecomplexes and their predicted Raman spectra computed at B3LYP/B1 theorylevel, where (A) represents dihydroxide 1, (B) represents monophosphate2, (C) represents axial monophosphate 3, and (D) represents diphosphate4;

FIG. 12 provides a possible mechanistic cycle of complex (R,R)-1c;

FIG. 13A and FIG. 13B depict the NMR spectra for Table 6 entries 2 and 3respectively;

FIG. 14 depicts a synthetic pathway for (R,R)-1c;

FIG. 15 depicts unsuccessful attempts to oxidize 2-sulfinyl esters usinga sulfenate anion strategy; and

FIG. 16 depicts the Infrared spectrum of (R,R)-1c.

FIG. 17 depicts the gram-scale synthesis pathway of armodafinil by using0.25 mol % of (R,R)-1b described in Example 13.

DESCRIPTION

As noted herein, two catalytic complexes for the sulfoxidation ofsulfides are disclosed herein that enable the sulfoxidation of a broadrange of substrate sulfides in enantioenriched forms.

The first of these systems is a complex of formula (I), comprising anorganic cation (A) and an inorganic anion (B):

wherein:

-   -   each R, independently represents C₁₋₃ alkyl-aryl or C₁₋₃        alkyl-Het^(a), which aryl or Het^(a) groups are unsubstituted or        are substituted by from one to five R₃ substituents;        each R₂ independently represents aryl, which group is        unsubstituted or substituted by from one to five R₄        substituents;    -   Het^(a) represents a 4- to 14-membered heterocyclic group        containing one or more heteroatoms selected from O, S and N,        which heterocyclic group may comprise one, two or three rings;    -   each R₃ and R₄ independently represents halo, branched or        unbranched C₁₋₆ alkyl, branched or unbranched C₂₋₆ alkenyl,        branched or unbranched C₂₋₆ alkynyl; C₃₋₆ cycloalkyl, aryl        (which latter five groups are unsubstituted or substituted by        one or more halogen atoms) or OR₅;    -   R₅ represents H, branched or unbranched C₁₋₆ alkyl, branched or        unbranched C₂₋₆ alkenyl, branched or unbranched C₂₋₆ alkynyl,        C₃₋₆ cycloalkyl or aryl (which latter five groups are        unsubstituted or substituted by one or more halogen atoms).

The second of these systems is a complex of formula (III), comprising anorganic cation (C) and an inorganic anion (D):

wherein:

-   -   each R₂₁ independently represents C₁₋₃ alkyl-aryl or C₁₋₃        alkyl-Het^(d), which aryl or Het^(d) groups are unsubstituted or        are substituted by from one to five R₂₃ substituents;    -   each R₂₂ independently represents aryl, which group is        unsubstituted or substituted by from one to five R₂₄        substituents;    -   Het^(d) represents a 4- to 14-membered heterocyclic group        containing one or more heteroatoms selected from O, S and N,        which heterocyclic group may comprise one, two or three rings;    -   each R₂₃ and R₂₄ independently represents halo, branched or        unbranched C₁₋₆ alkyl, branched or unbranched C₂₋₆ alkenyl,        branched or unbranched C₂₋₆ alkynyl; C₃₋₆ cycloalkyl, aryl        (which latter five groups are unsubstituted or substituted by        one or more halogen atoms) or OR₂₅;    -   R₂₅ represents H, branched or unbranched C₁₋₆ alkyl, branched or        unbranched C₂₋₆ alkenyl, branched or unbranched C₂₋₆ alkynyl,        C₃₋₆ cycloalkyl or aryl (which latter five groups are        unsubstituted or substituted by one or more halogen atoms).°

As mentioned above, also encompassed by the complexes of formulae I andIII are any solvates thereof. Preferred solvates are solvates formed bythe incorporation into the solid state structure (e.g. crystalstructure) of the compounds of the invention of molecules of aacceptable solvent (referred to below as the solvating solvent).Examples of such solvents include water, alcohols (such as methanol,ethanol, isopropanol and butanol), nitriles (such as acetonitrile,propionitrile, and butyronitrile), esters (such as ethyl acetate),ketones (such as acetone and ethyl methyl ketone), anddimethylsulphoxide. Solvates can be prepared by recrystallising thecompounds of the invention with a solvent or mixture of solventscontaining the solvating solvent. Whether or not a solvate has beenformed in any given instance can be determined by subjecting crystals ofthe compound to analysis using well-known and standard techniques suchas thermogravimetric analysis (TGA), differential scanning calorimetry(DSC) and X-ray crystallography.

The solvates can be stoichiometric or non-stoichiometric solvates.Particularly preferred solvates are hydrates, and examples of hydratesinclude hemihydrates, monohydrates and dihydrates.

For a more detailed discussion of solvates and the methods used to makeand characterise them, see Bryn et al., Solid-State Chemistry of Drugs,Second Edition, published by SSCI, Inc of West Lafayette, Ind., USA,1999, ISBN 0-967-06710-3.

Complexes of formula I, as well as solvates of such complexes are, forthe sake of brevity, hereinafter referred to together as the “compoundsof formula I”. Complexes of formula III, as well as solvates of suchcompleses are, for the sake of brevity, hereinafter referred to togetheras the “compounds of formula III”.

Compounds of formula I and formula III (as well as the compounds offormula II and IV as described hereinbelow) may contain double bonds andmay thus exist as E (entgegen) and Z (zusammen) geometric isomers abouteach individual double bond. All such isomers and mixtures thereof areincluded within the scope of the invention.

Compounds of formula I and formula III (as well as the compounds offormula II and IV as described hereinbelow) may exist as regioisomersand may also exhibit tautomerism. All tautomeric forms and mixturesthereof are included within the scope of the invention.

Compounds of formula I and formula III may contain one or moreasymmetric carbon atoms and may therefore exhibit optical and/ordiastereoisomerism. Diastereoisomers may be separated using conventionaltechniques, e.g. chromatography or fractional crystallisation.

The various stereoisomers may be isolated by separation of a racemic orother mixture of the compounds using conventional, e.g. fractionalcrystallisation or HPLC, techniques. Alternatively the desired opticalisomers may be made by reaction of the appropriate optically activestarting materials under conditions which will not cause racemisation orepimerisation (i.e. a ‘chiral pool’ method), by reaction of theappropriate starting material with a ‘chiral auxiliary’ which cansubsequently be removed at a suitable stage, by derivatisation (i.e. aresolution, including a dynamic resolution), for example with ahomochiral acid followed by separation of the diastereomeric derivativesby conventional means such as chromatography, or by reaction with anappropriate chiral reagent or chiral catalyst all under conditions knownto the skilled person. All stereoisomers and mixtures thereof areincluded within the scope of the invention.

Unless otherwise stated, the term “alkyl” refers to an acyclicunbranched or branched, or cyclic, hydrocarbyl radical, which may besubstituted or unsubstituted (with, for example, one or more haloatoms). Unless otherwise stated, where the term “alkyl” refers to anacyclic group, it is preferably C₁₋₆ alkyl (such as ethyl, propyl (e.g.n-propyl or isopropyl), butyl (e.g. branched or unbranched butyl),pentyl or, more preferably, methyl). Unless otherwise stated, where theterm “alkyl” is a cyclic group (which may be where the group“cycloalkyl” is specified), it is preferably C₃₋₆ cycloalkyl.

Unless otherwise stated, the term “alkenyl” refers to an acyclicunbranched or branched, or cyclic, hydrocarbyl radical containing one ormore carbon to carbon double bonds, and which radical may be substitutedor unsubstituted (with, for example, one or more halo atoms). Unlessotherwise stated, where the term “alkenyl” refers to an acyclic group,it is preferably C₂₋₆alkenyl (such as ethylenyl, propylenyl (e.g.n-propylenyl or isopropylenyl), butylenyl (e.g. branched or unbranchedbutylenyl), or pentylenyl). Unless otherwise stated, where the term“alkenyl” is a cyclic group (which may be where the group “cycloalkenyl”is specified), it is preferably C₄₋₆ cycloalkenyl.

Unless otherwise stated, the term “alkynyl” refers to an acyclicunbranched or branched hydrocarbyl radical containing one or more carbonto carbon triple bonds and may also contain one or more carbon to carbondouble bonds, and which radical may be substituted or unsubstituted(with, for example, one or more halo atoms). Unless otherwise stated,where the term “alkynyl” is used herein, it is preferably C₂₋₆ alkynyl(such as ethylynyl, propylynyl, butylynyl, or pentylynyl).

The term “halogen”, when used herein, includes fluorine, chlorine,bromine and iodine.

The term “aryl” when used herein includes C₆₋₁₄ (such as C₆₋₁₃ (e.g.C₆₋₁₀)) aryl groups, which may be substituted or unsubstituted. Suchgroups may be monocyclic, bicyclic or tricyclic and have between 6 and14 ring carbon atoms, in which at least one ring is aromatic. The pointof attachment of aryl groups may be via any atom of the ring system.However, when aryl groups are bicyclic or tricyclic, they are linked tothe rest of the molecule via an aromatic ring. C₆₋₁₄ aryl groups includephenyl, naphthyl and the like, such as 1,2,3,4-tetrahydronaphthyl,indanyl, indenyl and fluorenyl. The most preferred aryl groups includephenyl.

Heterocyclic (Het^(a) and Het^(d)) groups may be fully saturated, partlyunsaturated, wholly aromatic or partly aromatic in character. Values ofHet^(a) and Het^(d) groups that may be mentioned include acridinyl,1-azabicyclo[2.2.2]octanyl, azetidinyl, benzimidazolyl,benzisothiazolyl, benzisoxazolyl, benzodioxanyl, benzodioxepanyl,benzodioxepinyl, benzodioxolyl, benzofuranyl, benzofurazanyl,benzo[c]isoxazolidinyl, benzomorpholinyl, 2,1,3-benzoxadiazolyl,benzoxazinyl (including 3,4-dihydro-2H-1,4-benzoxazinyl),benzoxazolidinyl, benzoxazolyl, benzopyrazolyl, benzo[e]pyrimidine,2,1,3-benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl,carbazolyl, chromanyl, chromenyl, cinnolinyl, 2,3-dihydrobenzimidazolyl,2,3-dihydrobenzo[6]furanyl, 1,3-dihydrobenzo[c]furanyl,1,3-dihydro-2,1-benzisoxazolyl, 2,3-dihydropyrrolo[2,3-b]pyridinyl,dioxanyl, furanyl, furazanyl, hexahydropyrimidinyl, hydantoinyl,imidazolyl, imidazo[1,2-a]pyridinyl, imidazo[2,3-b]thiazolyl, indazolyl,indolinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolinyl,isoindolyl, isoquinolinyl, isothiaziolyl, isothiochromanyl,isoxazolidinyl, isoxazolyl, maleimido, morpholinyl,naphtho[1,2-b]furanyl, naphthyridinyl (including 1,6-naphthyridinyl or,particularly, 1,5-naphthyridinyl and 1,8-naphthyridinyl), oxadiazolyl,1,2- or 1,3-oxazinanyl, oxazolyl, oxetanyl, phenazinyl, phenothiazinyl,phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl,pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl,pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, pyrrolo[2,3-b]pyridinyl,pyrrolo[5,1-b]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolyl,quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl, sulfolanyl,3-sulfolenyl, 4,5,6,7-tetrahydrobenzimidazolyl,4,5,6,7-tetrahydrobenzopyrazolyl, 5,6,7,8-tetrahydrobenzo[e]pyrimidine,tetrahydrofuranyl, tetrahydroisoquinolinyl (including1,2,3,4-tetrahydroisoquinolinyl and 5,6,7,8-tetrahydroisoquinolinyl),tetrahydropyranyl, 3,4,5,6-tetrahydropyridinyl,1,2,3,4-tetrahydropyrimidinyl, 3,4,5,6-tetrahydropyrimidinyl,tetrahydroquinolinyl (including 1,2,3,4-tetrahydroquinolinyl and5,6,7,8-tetrahydroquinolinyl), tetrazolyl, thiadiazolyl, thiazolidinyl,thiazolyl, thienyl, thieno[5,1-c]pyridinyl, thiochromanyl, thiophenetyl,triazolyl, 1,3,4-triazolo[2,3-b]pyrimidinyl, xanthenyl and the like.Particular values of Het^(a) and Het^(d) that may be mentioned includethe 4- to 10-membered heterocyclic groups from the list above. Further,values of Het^(a) and Het^(d) that may be mentioned include the 5- and8-membered (e.g. 5- to 6-membered) heterocyclic groups from the listabove.

Substituents on heterocyclic (Het^(a) to Het^(f) (Het^(b) and Het^(c)are found in the compounds of formula II below, while Het^(e) andHet^(f) are found in the compounds of formula IV below)) groups may,where appropriate, be located on any atom in the ring system including aheteroatom. The point of attachment of heterocyclic groups may be viaany atom in the ring system including (where appropriate) a heteroatom(such as a nitrogen atom), or an atom on any fused carbocyclic ring thatmay be present as part of the ring system. Heterocyclic groups may alsobe in the N- or S-oxidised form.

For the avoidance of doubt, in cases in which the identity of two ormore substituents in a compound of formula I may be the same, the actualidentities of the respective substituents are not in any wayinterdependent. For example, given that the compound of formula I hasmore than four R₂ groups, those R₂ groups may be the same or different.Similarly, in the situation in which R₄ and R₅ are both C₂ alkyl groupssubstituted by one or more C₁₋₄ alkyl groups, the alkyl groups inquestion may be the same or different.

All individual features (e.g. preferred or particular features)mentioned herein may be taken in isolation or in combination with anyother feature (including preferred or particular features) mentionedherein (hence, preferred or particular features may be taken inconjunction with other preferred or particular features, orindependently of them).

Embodiments of the invention that may be mentioned include those thatrelate to compounds of formula I in which:

-   -   (a) each R₁ independently represents C₁₋₃alkyl-phenyl, which        phenyl group is substituted by from two to four R₃ substituents;    -   each R₂ independently represents phenyl, which group is        unsubstituted or substituted by from one to two R₄ substituents;    -   each R₃ and R₄ independently represents fluoro, branched or        unbranched C₁₋₆ alkyl, C₃₋₆ cycloalkyl, which latter two groups        are unsubstituted or substituted by one or more halogen atoms)        or OR₅;    -   R₅ represents branched or unbranched C₁₋₃ alkyl or C₃₋₆        cycloalkyl, which groups are unsubstituted or substituted by one        or more halogen atoms;    -   (b) each R₁ independently represents CH₂-phenyl, which phenyl        group is substituted by from two to three R₃ substituents;    -   each R₂ independently represents unsubstituted phenyl;    -   each R₃ independently represents fluoro, branched or unbranched        C₃₋₅ alkyl, which latter group is unsubstituted or OR₅;    -   R₅ represents branched or unbranched C₁₋₃ alkyl, which group is        unsubstituted or substituted by one or more halogen atoms;    -   (c) the organic cation (A) may be enantioenriched.

Embodiments of the invention that may be mentioned include those thatrelate to compounds of formula III in which:

-   -   (a) each R₂₁ independently represents C₁₋₃ alkyl-phenyl, which        phenyl group is substituted by from two to four R₂₃        substituents;    -   each R₂₂ independently represents phenyl, which group is        unsubstituted or substituted by from one to two R₂₄        substituents;    -   each R₂₃ and R₂₄ independently represents fluoro, branched or        unbranched C₁₋₆ alkyl, C₃₋₆ cycloalkyl, which latter two groups        are unsubstituted or substituted by one or more halogen atoms)        or OR₂₅;    -   R₂₅ represents branched or unbranched C₁₋₃ alkyl or C₃₋₆        cycloalkyl, which groups are unsubstituted or substituted by one        or more halogen atoms;    -   (b) each R₂₁ independently represents CH₂-phenyl, which phenyl        group is substituted by from two to three R₂₃ substituents;    -   each R₂₂ independently represents unsubstituted phenyl;    -   each R₂₃ independently represents fluoro, branched or unbranched        C₃₋₅ alkyl, which latter group is unsubstituted or OR₂₅;    -   R₂₅ represents branched or unbranched C₁₋₃ alkyl, which group is        unsubstituted or substituted by one or more halogen atoms;    -   (c) the organic cation (C) may be enantioenriched.

Embodiments of the invention that may be mentioned include those thatrelate to compounds of formula I in which the organic cation (A) orcompounds of formula III in which the organic cation (C) may be selectedfrom:

-   (i)    1,4-bis((4S,5S)-1,3-bis(3,5-di-tert-butylbenzyl)-4,5-diphenylimidazolidin-2-ylidene)piperazine-1,4-diium;-   (ii)    1,4-bis((4R,5R)-1,3-bis(3,5-di-tert-butylbenzyl)-4,5-diphenylimidazolidin-2-ylidene)piperazine-1,4-diium;-   (iii)    1,4-bis((4S,5S)-1,3-bis(3,5-di-tert-butyl-4-methoxybenzyl)-4,5-diphenylimidazolidin-2-ylidene)piperazine-1,4-diium;-   (iv)    1,4-bis((4R,5R)-1,3-bis(3,5-di-tert-butyl-4-methoxybenzyl)-4,5-diphenylimidazolidin-2-ylidene)piperazine-1,4-diium;-   (v)    1,4-bis((4S,5S)-1,3-bis(3,5-di-tert-butyl-4-fluorobenzyl)-4,5-diphenylimidazolidin-2-ylidene)piperazine-1,4-diium;    and-   (vi)    1,4-bis((4R,5R)-1,3-bis(3,5-di-tert-butyl-4-fluorobenzyl)-4,5-diphenylimidazolidin-2-ylidene)piperazine-1,4-diium.

For example, the organic cation (A)/(C) may be selected from:

-   (i)    1,4-bis((4S,5S)-1,3-bis(3,5-di-tert-butylbenzyl)-4,5-diphenylimidazolidin-2-ylidene)piperazine-1,4-diium;    and-   (ii)    1,4-bis((4R,5R)-1,3-bis(3,5-di-tert-butylbenzyl)-4,5-diphenylimidazolidin-2-ylidene)piperazine-1,4-diium.

As mentioned above, the compounds of formula I are useful in catalysingthe sulfoxidation of sulfides. As such, there is provided a process ofmanufacturing a sulfoxide, comprising reacting a compound of formula(II):

in the presence of a complex of formula (I), as defined hereinbefore,wherein in the compound of formula (II):

-   -   R₆ represents H, branched or unbranched C₁₋₆ alkyl, branched or        unbranched C₂₋₆ alkenyl, branched or unbranched C₂₋₆ alkynyl,        C₃₋₆ cycloalkyl (which latter three groups are unsubstituted or        substituted by one or more substituents selected from halo, OR₈,        and C(O)R₉), C(O)R₁₀, C(O)OR₁₁ or OR₁₂;    -   R₇ represents CH(R₁₃)(R₁₄), Het^(b) or aryl, which latter two        groups are unsubstituted or substituted by one or more        substituents selected from halo, NO₂, CN, branched or unbranched        C₁₋₆ alkyl (optionally substituted by one or more halo atoms),        C(O)R₅ or OR₁₆;    -   R₁₃ and R₁₄ each independently represent H, aryl or Het^(c)        (which latter two groups are unsubstituted or substituted by one        or more substituents selected from halo, branched or unbranched        C₁₋₆ alkyl, C(O)R₁₇ and OR₁₈), provided that at least one of R₁₃        and R₁₄ is not H;    -   R₈, R₁₂, R₁₆ and R₁₈ each independently represent H, C(O)R₁₉ or        a branched or unbranched C₁₋₆ alkyl optionally substituted by        one or more halo atoms;    -   R₉, R₁₀, R₁₅ and R₁₇ each independently represent a branched or        unbranched C₁₋₆ alkyl (optionally substituted by one or more        halo atoms), OR₂₀ or N(R_(20′))(R_(20″));    -   R₁₁ represents a branched or unbranched C₁₋₆ alkyl (optionally        substituted by one or more halo atoms);    -   R₁₉, R₂₀, R_(20′) and R_(20″) each independently represent H or        a branched or unbranched C₁₋₆ alkyl (optionally substituted by        one or more halo atoms);    -   Het^(b) and Het^(c) represents a 4- to 14-membered        heteroaromatic group containing one or more heteroatoms selected        from O, S and N, which heteroaromatic group may comprise one,        two or three rings; and        n represents from 1 to 10.

The terms “alkyl”, “alkenyl”, “alkynyl”, “aryl”, and “cycloalkyl” are asdefined hereinbefore.

Heterocyclic (Het^(b) and Het^(c)) groups are wholly aromatic or partlyaromatic in character and may be selected from the wholly aromatic orpartly aromatic heterocyclic (e.g. wholly aromatic) groups mentionedhereinabove with respect to Het^(a) and Het^(d) groups. Particularvalues of Het^(b) and Het^(c) that may be mentioned include the 4- to10-membered wholly aromatic or partly aromatic heterocyclic (e.g. whollyaromatic) groups mentioned in the list mentioned hereinabove withrespect to Het^(a) and Het^(d). Further, values of Het^(b) and Het^(c)that may be mentioned include the 5- and 8-membered (e.g. 5- to6-membered) wholly aromatic or partly aromatic heterocyclic (e.g. whollyaromatic) groups mentioned in the list mentioned hereinabove withrespect to Het^(a) and Het^(d).

In embodiments of the current invention, the compound of formula (II)may be one in which:

-   -   (a) R₆ represents branched or unbranched C₁₋₄ alkyl, branched or        unbranched C₂₋₄ alkenyl (which groups are unsubstituted or        substituted by one or more substituents selected from halo, and        C(O)R₉), C(O)R₁₀, or C(O)OR₁₁;    -   R₉ and R₁₀ each independently represent a branched or unbranched        C₁₋₄ alkyl (optionally substituted by one or more halo atoms) or        OR₂₀;    -   R₁₁ represents a branched or unbranched C₁₋₄ alkyl (optionally        substituted by one or more halo atoms)    -   (e.g. R₆ represents branched or unbranched branched or        unbranched C₂₋₄ alkenyl (which groups are unsubstituted or        substituted by one or more substituents selected from C(O)OR₂₀),        or C(O)OR₁₁;    -   R₁₁ and R₂₀ each independently represent a branched or        unbranched C₁₋₄ alkyl (e.g. Me, Et, or ^(t)Bu); and    -   n represents from 1 to 5);    -   (b) R₇ represents CH(R₁₃)(R₁₄), phenyl or napthyl, which latter        two groups are unsubstituted or substituted by one or more        substituents selected from halo, branched or unbranched C₁₋₆        alkyl (optionally substituted by one or more halo atoms),        C(O)R₁₅ or OR₁₆;    -   R₁₃ and R₁₄ each independently represent H, phenyl or naphtyl        (which latter two groups are unsubstituted or substituted by one        or more substituents selected from halo, branched or unbranched        C₁₋₃ alkyl, C(O)R₁₇ and OR₁₈), provided that at least one of R₁₃        and R₁₄ is not H.

In the process described herein using the compounds of formula I as acatalyst, the process may provide an enantiomerically enriched sulfoxideas the product where the compound of formula (I) comprises anenantioenriched organic cation (A)

As noted hereinbefore, the complex of formula (I) may be used in acatalytic amount or a stoichiometric amount. When used in a catalyticamount, the compound of formula (I) is used in combination with at leastone molar equivalent, relative to the compound of formula (II), of anoxidising agent. A suitable oxidising agent may be a peroxide, such asan organic peroxide or, more particularly, hydrogen peroxide.

In embodiments of the invention where the complex of formula (I) is usedin a catalytic amount in the process of oxidising compounds of formula(II), a suitable catalytic amount may be from 1 to 10 mol % relative tothe molar amount of the compound of formula (II) (e.g. 1 mol %).

It will be appreciated that the process described hereinbefore may beconducted in a suitable solvent. Solvents that may be mentioned hereininclude, but are not limited to toluene, xylene or, more particularly,an ether solvent (e.g. diethyl ether, diisopropyl ether or di-n-butylether). The process may be run at any suitable temperature up to theboiling point of the solvent (or solvents) used in the process. Forexample, the process may be conducted at a temperature of from −75° C.to 100° C., such as from −10° C. to 30° C. (e.g. from 0° C. to 25° C.).It will be appreciated that when the desired product of the process is asulfoxide that is enentioenriched, the process may be run at atemperature in the range of from −10° C. to 30° C., such as from 0° C.to 25° C.

While the complex of formula I may be pre-prepared, it is also possibleto generate the complex in situ. Thus in certain embodiments that may bementioned herein, the process may provide the complex of formula (I) insitu through reaction of an organic cation (A) with amolybdenum-containing salt and a sulfur-containing additive where:

-   -   the organic cation (A) is provided as a salt with a counterion        selected from chloride;    -   the molybdenum-containing salt is M₂MoO₄ or (NH₄)₆MoO₂₄ or        solvates thereof, where M represents Na, K or Li; and    -   the sulfur-containing additive is selected from one or more of        the group consisting of NaHSO₄, KHSO₄, H₂SO₄, and TBAHSO₄.

For example:

-   -   (i) the organic cation salt may be provided in an amount of from        1 to 10 mol % relative to the molar amount of the compound of        formula (II) (e.g. 1 mol %); and/or    -   (ii) the molybdenum-containing salt may be present in an amount        of from 1 mol % to 20 mol % relative to the molar amount of the        compound of formula (II) (e.g. from 2 mol % to 5 mol %, such as        2.5 mol %); and/or    -   (iii) the sulfur-containing additive may be present in an amount        of from 5 mol % to 100 mol % relative to the molar amount of the        compound of formula (II) (e.g. from 10 mol % to 55 mol %, such        as from 25 mol % to 50 mol %).

As mentioned above, the compounds of formula III are useful incatalysing the sulfoxidation of sulfides. As such, there is provided aprocess of manufacturing a sulfoxide, comprising reacting a compound offormula (IV):

in the presence of a catalytic amount of a complex of formula (III), asdefined in hereinbefore, and at least one molar equivalent of anoxidising agent relative to the compound of formula (IV), wherein in thecompound of formula (IV):

-   -   R₂₆ represents H, branched or unbranched C₁₋₆ alkyl, branched or        unbranched C₂₋₆ alkenyl, branched or unbranched C₂₋₆ alkynyl,        C₃₋₆ cycloalkyl, aryl, Het^(e) (which latter five groups are        unsubstituted or substituted by one or more substituents        selected from halo, NO₂, CN, C₁₋₆ alkyl (optionally substituted        by one or more halo atoms), and OR₂₈), OR₂₉, CN, or C(O)OR₃₀;    -   R₂₇ represents Het^(f) or aryl, which groups are unsubstituted        or substituted by one or more substituents selected from halo,        NO₂, CN, branched or unbranched C₁₋₆ alkyl (optionally        substituted by one or more halo atoms), or OR₃₁;    -   R₂₈, R₂₉ and R₃₁ each independently represent H, C(O)R₃₂ or a        branched or unbranched C₁₋₆ alkyl optionally substituted by one        or more halo atoms;    -   R₃₀ and R₃₂ each independently represent H or a branched or        unbranched C₁₋₆ alkyl optionally substituted by one or more halo        atoms;    -   each Het^(e) independently represents a 4- to 14-membered        heterocyclic group containing one or more heteroatoms selected        from O, S and N, which heterocyclic group may comprise one, two        or three rings; and    -   Het^(f) represents a 4- to 14-membered heteroaromatic group        containing one or more heteroatoms selected from O, S and N,        which heteroaromatic group may comprise one, two or three rings;        and        n represents from 1 to 10.

Heterocyclic (Het^(e) and Het^(f)) groups are wholly aromatic or partlyaromatic in character and may be selected from the wholly aromatic orpartly aromatic heterocyclic (e.g. wholly aromatic) groups mentionedhereinabove with respect to Het^(a) and Het^(d) groups. Particularvalues of Het^(e) and Het^(f) that may be mentioned include the 4- to10-membered wholly aromatic or partly aromatic heterocyclic (e.g. whollyaromatic) groups mentioned in the list mentioned hereinabove withrespect to Het^(a) and Het^(d). Further, values of Het^(e) and Het^(f)that may be mentioned include the 5- and 8-membered (e.g. 5- to6-membered) wholly aromatic or partly aromatic heterocyclic (e.g. whollyaromatic) groups mentioned in the list mentioned hereinabove withrespect to Het^(a) and Het^(d).

In embodiments of the current invention, the compound of formula (IV)may be one in which:

-   -   (a) R₂₆ represents H, phenyl, naphthyl, Het^(e) (which latter        three groups are unsubstituted or substituted by one or more        substituents selected from halo, NO₂, C₁₋₄ alkyl (optionally        substituted by one or more halo atoms), and OR₂₈), CN, or        C(O)OR₃₀;    -   each R₂₈ independently represents H, or a branched or unbranched        C₁₋₄ alkyl optionally substituted by one or more halo atoms; and    -   each R₃₀ independently represents a branched or unbranched C₁₋₄        alkyl (e.g. Me, Et, ^(t)Bu); and    -   n represents from 1 to 6    -   (e.g. R₂₆ represents H, phenyl, naphthyl (which latter two        groups are unsubstituted or substituted by one or more        substituents selected from halo, NO₂, C₁₋₄ alkyl (optionally        substituted by one or more halo atoms), and OR₂₈), dioxolanyl,        CN, or C(O)OR₃₀; and    -   each R₂₈ independently represents a branched or unbranched C₁₋₄        alkyl optionally substituted by one or more halo atoms (e.g.        CH₃, CH₂CF₃); and    -   n represents from 1 to 5);    -   (b) R₂₇ represents Het^(f), phenyl or naphthyl, which groups are        unsubstituted or substituted by one or more substituents        selected from F and C₁₋₄ alkyl (optionally substituted by one or        more halo atoms);    -   Het^(f) independently represents a 5- to 10-membered        heteroaromatic group containing one or more heteroatoms selected        from S and N, which heteroaromatic group may comprise one or two        rings (e.g. Het^(f) represents, thiazolyl, pyrrolyl, imidazolyl,        thiazolyl, pyridyl, benzimidazolyl, benzathiazolyl, or indolyl).

In the process described herein the process may provide anenantiomerically enriched sulfoxide as the product, where the compoundof formula (III) comprises an enantioenriched organic cation (C)

In certain embodiments that may be mentioned herein, the process mayprovide the complex of formula (III) in situ through reaction of anorganic cation (C) with M₂WO₄ and NaH₂PO₄, where:

-   -   the organic cation (C) is provided as a salt with a counterion        selected from chloride; and    -   M represents Na, K, NH₄ or Ag (e.g. Ag).

For example:

-   -   (i) the organic cation salt may be provided in an amount of from        1 to 10 mol % relative to the molar amount of the compound of        formula (IV) (e.g. 2 mol %); and/or    -   (ii) M₂WO₄ may be present in an amount of from 1 mol % to 20 mol        % relative to the molar amount of the compound of formula (IV)        (e.g. from 2 mol % to 5 mol %, such as 2 mol %); and/or    -   (iii) NaH₂PO₄ may be present in an amount of from 4 mol % to 50        mol % relative to the molar amount of the compound of        formula (IV) (e.g. from 5 mol % to 15 mol %, such as 10 mol %);    -   (iv) the molar ratio of NaH₂PO₄ to M₂WO₄ is from 2:1 to 10:1,        such as 5:1.

As noted hereinbefore, the complex of formula (III) may be used in acatalytic amount and so is used in combination with at least one molarequivalent, relative to the compound of formula (IV), of an oxidisingagent. A suitable oxidising agent may be a peroxide, such as an organicperoxide or, more particularly, hydrogen peroxide.

In embodiments of the invention where the complex of formula (III) isused in a catalytic amount in the process of oxidising compounds offormula (IV), a suitable catalytic amount may be from 1 to 10 mol %relative to the molar amount of the compound of formula (IV) (e.g. 1 mol%).

It will be appreciated that the process described hereinbefore may beconducted in a suitable solvent. Solvents that may be mentioned hereininclude, but are not limited to an ether solvent (e.g. diethyl ether,diisopropyl ether or di-n-butyl ether, such as diethyl ether or, moreparticularly, diisopropyl ether). The process may be run at any suitabletemperature up to the boiling point of the solvent (or solvents) used inthe process. For example, the process may be conducted at a temperatureof from −75° C. to 100° C., such as from −10° C. to 10° C. (e.g. from 0°C. to 5° C.). It will be appreciated that when the desired product ofthe process is a sulfoxide that is enentioenriched, the process may berun at a temperature in the range of from −10° C. to 10° C., such asfrom 0° C. to 5° C.

Compounds of formula I to IV may be prepared in accordance withtechniques that are well known to those skilled in the art, for exampleas described hereinafter in the examples section.

Substituents, such as R² in final compounds of formula I (or precursorsthereto and other relevant intermediates) may be modified one or moretimes, after or during the processes described hereinafter by way ofmethods that are well known to those skilled in the art. Examples ofsuch methods include substitutions, reductions (e.g. carbonyl bondreductions in the presence of suitable and, if necessary,chemoselective, reducing agents such as LiBH₄ or NaBH₄), oxidations,alkylations, acylations, hydrolyses, esterifications, andetherifications. The precursor groups can be changed to a different suchgroup, or to the groups defined in formula I, at any time during thereaction sequence.

Compounds of the invention may be isolated from their reaction mixturesusing conventional techniques (e.g. recrystallisation, columnchromatography, preparative HPLC, etc.).

In the processes described hereinafter, the functional groups ofintermediate compounds may need to be protected by protecting groups.

The protection and deprotection of functional groups may take placebefore or after a reaction in the above-mentioned schemes.

Protecting groups may be removed in accordance with techniques that arewell known to those skilled in the art and as described hereinafter. Forexample, protected compounds/intermediates described hereinafter may beconverted chemically to unprotected compounds using standarddeprotection techniques.

The type of chemistry involved will dictate the need, and type, ofprotecting groups as well as the sequence for accomplishing thesynthesis.

The use of protecting groups is fully described in “Protective Groups inOrganic Chemistry”, edited by J W F McOmie, Plenum Press (1973), and“Protective Groups in Organic Synthesis”, 3^(rd) edition, T. W. Greene &P. G. M. Wutz, Wiley-Interscience (1999).

As used herein, the term “functional groups” means, in the case ofunprotected functional groups, hydroxy-, thiolo-, amino function,carboxylic acid and, in the case of protected functional groups, loweralkoxy, N-, O-, S-acetyl, carboxylic acid ester.

Non-limiting examples that embody certain aspects of the invention willnow be described.

EXPERIMENTAL

General

¹H and ¹³C NMR spectra were recorded on Bruker Avance III 400 (400 MHz)(100 MHz) spectrometer. Chemical shifts are recorded as 6 in units ofparts per million (ppm). The residual solvent peak was used as aninternal reference. ³¹P NMR was performed on a Bruker Avance III 400(400 MHz) spectrometer. ¹⁹F NMR was performed on a Bruker Avance III 400(400 MHz) spectrometer. ⁹⁵Mo NMR was performed on a Bruker Avance III400 (26.7 MHz) spectrometer and chemical shifts are reported relative toan external reference 2 M Na₂MoO₄.2H₂O solution in D₂O, assigned to 0ppm.

High resolution mass spectra (HRMS) were obtained on the Q-Tof Premiermass spectrometer (Waters Corporation) and reported in units of mass tocharge ratio (m/z).

Enantiomeric excess values were determined by chiral HPLC analysis onShimadzu LC-20AT and LC-2010CHT HPLC workstations. Optical rotationswere measured in ethyl acetate using a 1 mL cell with a 1 dm path lengthon a Jasco P-1030 polarimeter with a sodium lamp of wavelength 589 nmand reported as follows: [a]Drt (c=g/100 mL, solvent).

Two-dimensional (2D) Raman spectral images were obtained by scanning theline-shaped laser focus in a single direction with a two-dimensionalimage sensor (Princeton Instrument, PIXIS 400 BR, −70° C., 1340×400pixels).

X-ray crystallography analysis was performed on Bruker X8 APEX X-raydiffraction meter.

Flash chromatography separations were performed on Merck 60 (0.040-0.063mm) mesh silica gel.

Analytical thin-layer chromatography (TLC) was performed on Merck 60F254 silica gel plates. Visualization was performed using a UV lamp orpotassium permanganate stain.

IR was recorded on neat compounds or in dispersed KBr pellets using aShimadzu IR Prestige21 FTIR spectrometer; only strong and selectedabsorbances (ν_(max)) are reported.

Melting point was recorded on OptiMelt (MPA100) melting point apparatus.

Materials

Toluene, Acetonitrile and Dichloromethane were distilled over CaH₂ underN₂ atmosphere. Unless otherwise stated, all reagents were purchased fromthe commercial suppliers Sigma-Aldrich or TCI. All racemates wereprepared using a stoichiometric amount of mCPBA(meta-chloroperoxybenzoic acid) in DCM by analogy to the proceduresreferenced in M. Michel, Tetrahedron, 1986, 42, 5464 and/or the generalprocedure for sulfoxidation set out in and B. Kohl et al., J. Med.Chem., 1992, 35, 1054.

THF was distilled over sodium/benzophenone under N₂ atmosphere. Themercaptans were purchased from commercial suppliers and used directlywithout further purification. Other reagents and solvents werecommercial grade and were used as supplied without further purification,unless otherwise stated. Experiments involving moisture and/or airsensitive components were performed under a positive pressure ofnitrogen in oven-dried glassware equipped with a rubber septum inlet.

Preparation of Catalysts and Substrates

Preparation and Characterization of Chiral Bisguanidinium

The preparation of catalyst BG-1 (also referred to as (S,S)-1a herein)is provided below as a representative example. Chiral bisguanidiniumsBG2-5 and (R,R)-1b were prepared by analogy.

1,4-bis((4S,5S)-1,3-bis(3,5-di-tert-butylbenzyl)-4,5-diphenylimidazolidin-2-ylidene)piperazine-1,4-diiumchloride (BG-1)

(4S,5S)-1,3-bis(3,5-di-tert-butylbenzyl)-4,5-diphenylimidazolidine-2-thionewas prepared in accordance with literature procedure (see Zong, L.; Ban,X.; Kee, C. W.; Tan, C. H. Angewandte. Chemie. 2014, 126, 12043). A 25mL round-bottomed flask was charged with a solution of(4S,5S)-1,3-bis(3,5-di-tert-butylbenzyl)-4,5-diphenylimidazolidine-2-thione(1.59 g, 2.41 mmol, 1.0 equiv) in toluene (8 mL) with a condenser underN₂ atmosphere. (COCl)₂ (1.66 mL, 19.3 mmol, 8.0 equiv) was added viasyringe in one portion. The mixture was heated to 90° C. for about 12 h,and then refluxed for 1 h. Toluene was removed under reduced pressureand solid imidazoline salt was obtained directly for the next stepwithout any purification. The imidazoline salt was dissolved in dry MeCN(2 mL) under nitrogen atmosphere, and then piperazine (62 mg, 0.72 mmol,0.3 equiv) was added, followed by the addition of Et₃N (1 mL, 7.23 mmol,3.0 equiv). Then the whole solution was heated to reflux for 12 h andcooled to rt. 1M HCl (20 mL) was added to the reaction solution and themixture was then extracted by CH₂Cl₂ (20 mL×3), and the organic layerswere combined and dried over anhydrous Na₂SO₄. Solvent was removed underreduced pressure and bis-guanidinium salt BG-1 was obtained by flashchromatography (silica gel, DCM-Methanol 100:1-30:1), as a beige powder.

1,4-bis((4S,5S)-1,3-bis(3,5-di-tert-butylbenzyl)-4,5-diphenylimidazolidin-2-ylidene)piperazine-1,4-diiumchloride (BG-1 or (S,S)-1a)

beige powder; 80% yield; mp: 209.3-211.5° C.; [a]_(D) ²²=−33.9 (c 1.07,CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 7.30 (dd, J=5.0, 1.5 Hz, 12H), 7.20(s, 4H), 7.05 (dd, J=6.5, 2.8 Hz, 8H), 6.96 (d, J=1.5 Hz, 8H), 5.19 (d,J=14.7 Hz, 4H), 4.82 (d, J=14.7 Hz, 4H), 4.73 (d, J=9.5 Hz, 4H), 4.48(d, J=9.5 Hz, 4H), 4.32 (s, 1H), 1.14 (s, 72H); ¹³C NMR (100 MHz, CDCl₃)δ 162.68, 151.30, 137.67, 131.89, 129.58, 129.16, 126.51, 123.37,122.26, 70.39, 54.52, 48.99, 34.69, 31.37, 31.28; IR: 2962.66, 1597.06,1527.62, 1454.33, 1361.74, 1018.41, 910.40, 740.64, 702.09 cm⁻¹; HRMS(ESI) calcd for C₉₄H₁₂₄Cl₂N₆ m/z [M−2Cl⁻]²⁺: 668.4944; found: 668.4941.

1,4-bis((4R,5R)-1,3-bis(3,5-di-tert-butylbenzyl)-4,5-diphenylimidazolidin-2-ylidene)piperazine-1,4-diiumchloride ((R,R)-1b)

beige powder; 70% yield; mp: 209.6-212.2° C.; [a]_(D) ²²=+31.9 (c 1.92,CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 7.29 (dd, J=5.1, 1.6 Hz, 12H), 7.20(s, 4H), 7.08-7.00 (m, 8H), 6.95 (d, J=1.6 Hz, 8H), 5.19 (d, J=14.6 Hz,4H), 4.80 (d, J=14.7 Hz, 4H), 4.72 (d, J=9.6 Hz, 4H), 4.47 (d, J=9.5 Hz,4H), 4.31 (s, 4H), 1.13 (s, 72H); ¹³C NMR (100 MHz, CDCl₃) δ 162.65,151.27, 137.68, 131.89, 129.54, 129.12, 126.48, 123.37, 122.24, 70.32,54.45, 48.98, 34.66, 31.25; IR: 2962.66, 1600.92, 1519.91, 1454.33,1361.74, 1280.73, 1199.72, 1153.43, 1018.41, 910.4, 736.81, 702.09 cm⁻¹;HRMS (ESI) calcd for C₉₄H₁₂₄Cl₂N₆ m/z [M−2Cl⁻]²⁺: 668.4944; found:668.4951.

Synthesis of Sulfide Substrates for Use in tungstate System Synthesis ofHeterocyclic Sulfides (2a-2u)

Benzyl bromide (3.6 mmol) was added to a solution of heterocyclic thiol(3 mmol) and Et₃N (4.5 mmol) dropwise in MeCN (10 mL) at roomtemperature. The resulting reaction mixture was stirred for appropriatetime (monitored by TLC). 6M HCl aqueous was used for quenching. Then themixture was extracted by Ethyl acetate EtOAc (10 mL×3). The combinedorganic layer was washed by brine and dried by Na₂SO₄. After removingsolvent under reduced pressure, the crude residue was directly loadedonto a short silica gel column, followed by gradient elution withHexane/EtOAc mixture (50/1-30/1 ratio). Removing the solvent in vacuo,afforded the desired products.

Phenyl sulfides (5a-5d) were prepared by analogy.

Synthesis of Heterocyclic Sulfide (3)

2-Mercaptobenzimidazole (1.0 mmol),2-(Chloromethyl)-3-methyl-4-(2,2,2-trifluoroethoxy)pyridinehydrochloride (1.0 mmol), NaOH (2.0 mmol) and NaI (0.033 mmol) wereadded to a ethanol and acetone mixed solvent (v:v, 3:1). After refluxingfor 1.5 hours, cool down to the room temperature. Filtrate the reactionmixture and dry the residues on rotary evaporators, then directly loadthe residues onto a short silica gel column, followed by gradientelution with Hexane/EtOAc mixture (30/1-15/1 ratio). Removing thesolvent in vacuo, afforded the desired products.

Synthesis and Characterization of Sulfide Substrates for Use inMolybdate System Synthesis of methyl 2-(benzhydrylthio)acetate (7a)

(see Andrea Altieri et al. Sulfur-containing amide-based [2]rotaxanesand molecular shuttles. Chem. Sci. 2, 1922-1928 (2011)):

Methyl thioglycolate (447 μL, 5.0 mmol) was slowly added tobromodiphenyl methane (1.359 g, 5.5 mmol) at room temperature. After theinitial reaction had subsided, the mixture was heated to 100° C. for 2 huntil there was no further evolution of HBr which was trapped andneutralized by passing over an aqueous saturated NaHCO₃ solution. Thereaction mixture was then allowed to cool to room temperature and pouredinto H₂O (10 mL) and extracted with EtOAc (25 mL×3). The combinedorganic layer was washed by brine and dried by Na₂SO₄, filtered andconcentrated. The crude residue was subjected to purification by flashcolumn chromatography (silica gel, hexane:EtOAc, gradient from 100:1 to20:1) to afford the product as pale yellow oil, 1.238 g, 91% yield. ¹HNMR (400 MHz, CDCl₃) δ 7.48-7.40 (m, 4H), 7.33 (dt, J=7.7, 5.2 Hz, 4H),7.28-7.19 (m, 2H), 5.40 (s, 1H), 3.68 (s, 3H), 3.10 (s, 2H); ¹³C NMR(100 MHz, CDCl₃) δ 170.71, 140.29, 128.61, 128.43, 127.45, 54.16, 52.29,33.48; IR: 1732.08, 1597.06, 1492.90, 1450.47, 1276.88, 1195.87,1130.29, 1006.84, 748.38, 702.09, 628.79, 586.36 cm⁻¹; HRMS (ESI) calcdfor C₁₆H₁₆O₂S m/z [M+H]⁺: 273.0949; found: 273.0946.

Synthesis of Aliphatic 2-thio Acetates (7b-7k). For example, synthesisof tert-butyl 2-(benzylthio)acetate (7b)

(see Qingping Zeng et al. Benzoheterocyclecarboxaldehyde derivatives asIRE-1a inhibitors and their preparation and use for the treatment ofdiseases. WO2011127070A2 (2011)):

Benzyl mercaptan (mg, 5.0 mmol) was dissolved in dry DMF (25 mL) and thesolution was cooled to 0° C. NaH (60% suspension in oil) (220 mg, 5.5mmol, 1.1 equiv) was then added and the resulting solution was stirredfor 30 min. tert-butyl bromoacetate (812 μL, 5.5 mmol, 1.1 equiv) wasthen added and the solution was stirred at room temperature forappropriate time. The reaction was quenched by slow addition of H₂O andDMF solvent was removed by vacuum pump. The resulting residue wassubjected to purification by flash column chromatography (silica gel,hexanes:EtOAc, 20:1) to afford the desired product with 80% toquantitative yield. Aliphatic 2-thio Acetates (7c-7k) are prepared byanalogy.

tert-butyl 2-(benzylthio)acetate (7b)

Colorless oil; ¹H NMR (400 MHz, CDCl₃) δ 7.37-7.29 (m, 4H), 7.28-7.21(m, 1H), 3.83 (s, 2H), 2.98 (s, 2H), 1.49 (s, 9H); ¹³C NMR (100 MHz,CDCl₃) δ 169.53, 137.39, 129.09, 128.46, 127.12, 81.46, 36.07, 33.39,27.97; IR: 1728.22, 1492.90, 1454.33, 1392.61, 1369.46, 1296.16,1257.59, 1122.57, 948.98, 852.54, 763.81, 702.09 cm⁻¹; HRMS (ESI) calcdfor C₁₃H₁₈O₂S m/z [M+H]⁺: 239.1106; found: 239.1103.

tert-butyl 2-((4-methylbenzyl)thio)acetate (7c)

Colorless oil; ¹H NMR (400 MHz, CDCl₃) δ 7.22 (d, J=8.0 Hz, 2H), 7.13(d, J=7.9 Hz, 2H), 3.80 (s, 2H), 2.98 (s, 2H), 2.34 (s, 3H), 1.49 (s,9H); ¹³C NMR (100 MHz, CDCl₃) δ 169.63, 136.80, 134.29, 129.17, 129.01,81.45, 35.82, 33.42, 28.00, 21.06; IR: 1728.22, 1512.19, 1454.33,1392.61, 1369.46, 1296.16, 1257.59, 1122.57, 948.98, 817.82, 725.23cm⁻¹; HRMS (ESI) calcd for C₁₄H₂₀O₂S m/z [M+H]⁺: 253.1262; found:253.1256.

tert-butyl 2-((4-methoxybenzyl)thio)acetate (7d)

Colorless oil; ¹H NMR (400 MHz, CDCl₃) δ 7.27 (d, J=8.3 Hz, 2H), 6.87(d, J=8.3 Hz, 2H), 3.81 (s, 3H), 3.80 (s, 2H), 2.99 (s, 2H), 1.51 (s,9H); ¹³C NMR (100 MHz, CDCl₃) δ 169.63, 158.73, 130.21, 129.32, 113.88,81.43, 55.22, 35.50, 33.33, 27.99; IR: 1728.22, 1716.65, 1612.49,1585.49, 1512.19, 1458.18, 1369.46, 1300.02, 1249.87, 1172.72, 1122.57,1033.85, 948.98, 833.25 cm⁻¹; HRMS (ESI) calcd for C₁₄H₂₀O₃S m/z [M+H]⁺:269.1211; found: 269.1208.

tert-butyl 2-((4-fluorobenzyl)thio)acetate (7e)

Colorless oil; ¹H NMR (400 MHz, CDCl₃) δ 7.36-7.27 (m, 2H), 7.06-6.96(m, 2H), 3.80 (s, 2H), 2.96 (s, 2H), 1.48 (s, 9H); ¹³C NMR (100 MHz,CDCl₃) δ 169.47, 161.98 (d, J=245.6 Hz), 133.15 (d, J=3.2 Hz), 130.68(d, J=8.1 Hz), 115.35 (d, J=21.5 Hz), 81.61, 35.34, 33.35, 28.00; ¹⁹FNMR (376 MHz, CDCl₃) δ −115.35; IR: 1728.22, 1600.92, 1508.33, 1392.61,1369.46, 1296.16, 1222.57, 1122.57, 948.98, 837.11, 759.95, 732.95 cm⁻¹;HRMS (ESI) calcd for C₁₃H₁₇FO₂S m/z [M+H]⁺: 257.1012; found: 257.1010.

tert-butyl 2-((4-chlorobenzyl)thio)acetate (7f)

Colorless oil; ¹H NMR (400 MHz, CDCl₃) δ 7.32-7.22 (m, 4H), 3.78 (s,2H), 2.95 (s, 2H), 1.48 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 169.39,135.95, 132.97, 130.46, 128.63, 81.64, 35.37, 33.31, 27.98; IR: 1728.22,1489.05, 1454.33, 1369.46, 1296.16, 1257.59, 1122.57, 1091.71, 1014.56,948.98, 833.25 cm⁻¹; HRMS (ESI) calcd for C₁₃H₁₇ClO₂S m/z [M+H]⁺:273.0716; found: 273.0710.

tert-butyl 2-((2-methylbenzyl)thio)acetate (7g)

Colorless oil; ¹H NMR (400 MHz, CDCl₃) δ 7.24 (d, J=6.6 Hz, 1H),7.20-7.11 (m, 3H), 3.85 (s, 2H), 3.03 (s, 2H), 2.41 (s, 3H), 1.51 (s,10H); 13C NMR (100 MHz, CDCl₃) δ 169.68, 136.85, 135.00, 130.69, 130.00,127.48, 125.76, 81.49, 34.27, 33.90, 27.99, 19.07; IR: 1716.65, 1454.33,1392.61, 1369.46, 1292.31, 1257.59, 1161.15, 1122.57, 948.98, 763.81,732.95, 489.92 cm⁻¹; HRMS (ESI) calcd for C₁₄H₂₀O₂S m/z [M+H]⁺:253.1262; found: 253.1270.

tert-butyl 2-((2-chlorobenzyl)thio)acetate (7h)

Colorless oil; ¹H NMR (400 MHz, CDCl₃) δ 7.42-7.33 (m, 2H), 7.24-7.15(m, 2H), 3.95 (s, 2H), 3.05 (s, 2H), 1.49 (s, 9H); ¹³C NMR (100 MHz,CDCl₃) δ 169.48, 135.21, 134.16, 131.04, 129.93, 128.62, 126.70, 81.66,33.88, 33.75, 27.99; IR: 1728.22, 1473.62, 1446.61, 1392.61, 1369.46,1296.16, 1257.59, 1161.15, 1130.29, 1037.70, 948.98, 763.81, 740.67cm⁻¹; HRMS (ESI) calcd for C₁₃H₁₇ClO₂S m/z [M+H]⁺: 273.0716; found:273.0720.

tert-butyl 2-((2-bromobenzyl)thio)acetate (7i)

Colorless oil; ¹H NMR (400 MHz, CDCl₃) δ 7.57 (dd, J=8.0, 1.1 Hz, 1H),7.39 (dd, J=7.6, 1.7 Hz, 1H), 7.27 (td, J=7.5, 1.2 Hz, 1H), 7.12 (td,J=7.7, 1.7 Hz, 1H), 3.96 (s, 2H), 3.05 (s, 2H), 1.49 (s, 9H); ¹³C NMR(100 MHz, CDCl₃) δ 169.51, 136.86, 133.29, 131.04, 128.84, 127.34,124.61, 81.68, 36.46, 33.87, 28.01; IR: 1728.22, 1469.76, 1369.46,1296.16, 1161.15, 1126.43, 1026.13, 948.98, 763.81, 736.81 cm⁻¹; HRMS(ESI) calcd for C₁₃H₁₇BrO₂S m/z [M+H]⁺: 317.0211; found: 317.0202.

tert-butyl 2-((thiophen-2-ylmethyl)thio)acetate (7j)

Pale yellow oil; ¹H NMR (400 MHz, CDCl₃) δ 7.22 (dd, J=5.1, 1.2 Hz, 1H),6.97 (dd, J=3.4, 0.9 Hz, 1H), 6.92 (dd, J=5.1, 3.5 Hz, 1H), 4.06 (s,2H), 3.06 (s, 2H), 1.49 (s, 10H); ¹³C NMR (100 MHz, CDCl₃) δ 169.36,140.48, 126.89, 126.62, 125.19, 81.60, 33.41, 30.43, 27.98; IR: 1728.22,1392.61, 1369.46, 1296.16, 1257.59, 1165.00, 1134.14, 948.98, 852.54,702.09 cm⁻¹; HRMS (ESI) calcd for C₁₁H₁₆O₂S₂ m/z [M+H]⁺: 245.0670;found: 245.0678.

tert-butyl 2-(tert-butylthio)acetate (7k)

Colorless oil; ¹H NMR (400 MHz, CDCl₃) δ 3.20 (s, 2H), 1.46 (s, 9H),1.33 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 170.38, 81.34, 42.81, 32.71,30.75, 27.91; IR: 1728.22, 1458.18, 1392.61, 1365.60, 1288.45, 1257.59,1172.72, 1130.29, 952.84, 837.11, 763.81 cm⁻¹; HRMS (ESI) calcd forC₁₀H₂₀O₂S m/z [M+H]⁺: 205.1262; found: 205.1259.

Synthesis of Aromatic 2-thio Acetates (9a-k)

For example, synthesis of tert-butyl 2-(phenylthio)acetate (9a) (seeKatsukiyo Miura, Naoki Fujisawa, Hiroshi Saito, Di Wang & Akira Hosomi.Synthetic Utility of Stannyl Enolates as Radical Alkylating Agents1.Org. Lett. 3, 2591-2594 (2001)):

A mixture of thiophenol (511 μL, 5.0 mmol), Et₃N (697 μL, 5.0 mmol),tert-butyl bromoacetate (738 μL, 5.0 mmol), and toluene (5 mL) wasstirred at room temperature for the appropriate time and monitored byTLC. After the addition of H₂O, the mixture was extracted with EtOAc.The combined organic layer was washed by brine and dried by Na₂SO₄,filtered and concentrated. The crude residue was subjected topurification by flash column chromatography (silica gel, hexanes:EtOAc,20:1) to afford the desired product with 90% to quantitative yield.Aromatic 2-thio Acetates (9b-k) are prepared by analogy.

tert-butyl 2-(phenylthio)acetate (9a)

Pale yellow oil; ¹H NMR (400 MHz, CDCl₃) δ 7.40 (d, J=7.7 Hz, 2H), 7.28(t, J=7.5 Hz, 2H), 7.20 (dd, J=8.3, 6.3 Hz, 1H), 3.55 (s, 2H), 1.39 (s,9H); ¹³C NMR (100 MHz, CDCl₃) δ 168.69, 135.23, 129.77, 128.82, 126.63,81.76, 37.63, 27.79; IR: 1728.22, 1585.49, 1481.33, 1392.61, 1369.46,1292.31, 1257.59, 1165.00, 1134.14, 948.98, 848.68 740.67, 690.52,489.92 cm⁻¹; HRMS (ESI) calcd for C₁₂H₁₆O₂S m/z [M+H]⁺: 225.0949; found:225.0948.

tert-butyl 2-(p-tolylthio)acetate (9b)

Colorless oil; 1H NMR (400 MHz, CDCl₃) δ 7.32 (d, J=8.1 Hz, 2H), 7.10(d, J=8.0 Hz, 2H), 3.50 (s, 2H), 2.32 (s, 3H), 1.40 (s, 9H); ¹³C NMR(100 MHz, CDCl₃) δ 168.91, 136.97, 131.48, 130.69, 129.64, 81.70, 38.38,27.86, 21.01; IR: 1728.22, 1492.90, 1454.33, 1392.61, 1369.46, 1292.31,1257.59, 1168.86, 1134.14, 948.98, 806.25 cm⁻¹; HRMS (ESI) calcd forC₁₃H₁₈O₂S m/z [M+H]⁺: 239.1106; found: 239.1109.

tert-butyl 2-((4-methoxyphenyl)thio)acetate (9c)

Colorless oil; ¹H NMR (400 MHz, CDCl₃) δ 7.41 (d, J=8.8 Hz, 2H), 6.84(d, J=8.8 Hz, 2H), 3.79 (s, 3H), 3.43 (s, 2H), 1.39 (s, 9H); 13C NMR(100 MHz, CDCl₃) δ 169.03, 159.44, 133.90, 125.30, 114.51, 81.56, 55.30,39.58, 27.88; IR: 1728.22, 1593.20, 1492.90, 1462.04, 1392.61, 1369.46,1288.45, 1246.02, 1172.72, 1130.29, 1029.99, 948.98, 829.39 cm⁻¹; HRMS(ESI) calcd for C₁₃H₁₈O₃S m/z [M+H]⁺: 255.1055; found: 255.1055.

tert-butyl 2-((4-fluorophenyl)thio)acetate (9d)

Colorless oil; ¹H NMR (400 MHz, CDCl₃) δ 7.51-7.32 (m, 2H), 7.06-6.89(m, 2H), 3.47 (s, 2H), 1.38 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 168.64,162.18 (d, J=247.3 Hz), 133.11 (d, J=8.1 Hz), 130.04 (d, J=3.4 Hz),115.97 (d, J=21.9 Hz), 81.82, 38.72, 27.82; ¹⁹F NMR (376 MHz, CDCl₃) δ−114.44; IR: 1728.22, 1589.34, 1492.90, 1454.33, 1392.61, 1369.46,1292.31, 1230.58, 1138.00, 1091.71, 948.98, 829.39, 628.79 cm⁻¹; HRMS(ESI) calcd for C₁₂H₁₅FO₂S m/z [M+H]⁺: 243.0855; found: 243.0853.

tert-butyl 2-((4-chlorophenyl)thio)acetate (9e)

Colorless oil; ¹H NMR (400 MHz, CDCl₃) δ 7.33 (d, J=8.6 Hz, 2H), 7.25(d, J=8.6 Hz, 2H), 3.52 (s, 2H), 1.40 (s, 9H); ¹³C NMR (100 MHz, CDCl₃)δ 168.48, 133.81, 132.81, 131.20, 129.01, 82.08, 37.78, 27.86; IR:1728.22, 1477.47, 1454.33, 1392.61, 1369.46, 1292.31, 1257.59, 1138.00,1095.57, 1010.70, 948.98, 817.82 cm⁻¹; HRMS (ESI) calcd for C₁₂H₁₅ClO₂Sm/z [M+H]*: 259.0560; found: 259.0553.

tert-butyl 2-((4-bromophenyl)thio)acetate (9f)

Colorless oil; 1H NMR (400 MHz, CDCl₃) δ 7.46-7.36 (m, 2H), 7.31-7.22(m, 2H), 3.52 (s, 2H), 1.40 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 168.41,134.53, 131.91, 131.24, 120.62, 82.08, 37.55, 27.84; IR: 1716.65,1454.33, 1392.61, 1369.46, 1288.45, 1257.59, 1130.29, 1091.71, 1068.56,1006.84, 948.98, 810.10 cm⁻¹; HRMS (ESI) calcd for C₁₂H₁₅BrO₂S m/z[M+H]⁺: 303.0054; found: 303.0051.

tert-butyl 2-(o-tolylthio)acetate (9g)

Colorless oil; ¹H NMR (400 MHz, CDCl₃) δ 7.41-7.33 (m, 1H), 7.22-7.08(m, 3H), 3.54 (s, 2H), 2.42 (s, 3H), 1.40 (s, 9H); ¹³C NMR (100 MHz,CDCl₃) δ 168.61, 137.99, 134.35, 130.07, 129.21, 126.49, 126.37, 81.73,36.83, 27.77, 20.29; IR: 1728.22, 1589.34, 1454.33, 1369.46, 1292.31,1257.59, 1165.00, 1130.29, 948.98, 748.38 cm⁻¹; HRMS (ESI) calcd forC₁₃H₁₈O₂S m/z [M+H]⁺: 239.1106; found: 239.1100.

tert-butyl 2-((2-methoxyphenyl)thio)acetate (9h)

Pale yellow oil; ¹H NMR (400 MHz, CDCl₃) δ 7.37 (d, J=7.6 Hz, 1H), 7.23(t, J=7.5 Hz, 1H), 6.90 (t, J=7.6 Hz, 1H), 6.86 (d, J=8.2 Hz, 1H), 3.89(s, 3H), 3.54 (s, 2H), 1.36 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 168.86,157.95, 131.56, 128.41, 122.71, 120.87, 110.59, 81.51, 55.73, 35.99,27.82; IR: 1728.22, 1712.79, 1581.63, 1454.33, 1392.61, 1369.46,1292.31, 1246.02, 1172.72, 1122.57, 1072.42, 1026.13, 952.84, 848.68,748.38, 682.80, 578.64 cm⁻¹; HRMS (ESI) calcd for C₁₃H₁₈O₃S m/z [M+H]⁺:255.1055; found: 255.1059.

tert-butyl 2-((2-chlorophenyl)thio)acetate (9i)

Pale yellow oil; ¹H NMR (400 MHz, CDCl₃) δ 7.41-7.31 (m, 2H), 7.20 (td,J=7.6, 1.5 Hz, 1H), 7.13 (td, J=7.6, 1.6 Hz, 1H), 3.59 (s, 2H), 1.39 (s,9H); ¹³C NMR (100 MHz, CDCl₃) δ 168.13, 134.45, 133.92, 129.67, 129.64,127.32, 127.05, 82.04, 36.17, 27.77; IR: 1728.22, 1577.77, 1454.33,1392.61, 1369.46, 1296.16, 1257.59, 1141.86, 1033.85, 948.98, 848.68,748.38 cm⁻¹; HRMS (ESI) calcd for C₁₂H₁₅ClO₂S m/z [M+H]⁺: 259.0560;found: 259.0563.

tert-butyl 2-(naphthalen-1-ylthio)acetate (9j)

Pale yellow solid; mp: 43.6-45.3° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.44 (d,J=8.4 Hz, 1H), 7.85 (d, J=8.1 Hz, 1H), 7.78 (d, J=8.2 Hz, 1H), 7.70 (d,J=7.1 Hz, 1H), 7.58 (t, J=7.1 Hz, 1H), 7.52 (t, J=7.2 Hz, 1H), 7.41 (t,J=7.7 Hz, 1H), 3.60 (s, 2H), 1.34 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ168.70, 133.94, 133.10, 132.18, 130.02, 128.58, 128.27, 126.62, 126.25,125.51, 125.11, 81.76, 38.19, 27.80; IR: 1728.22, 1566.20, 1504.48,1454.33, 1392.61, 1369.46, 1296.16, 1265.30, 1134.14, 948.98, 798.53,771.53, 740.67, 702.09 cm⁻¹; HRMS (ESI) calcd for C₁₆H₁₈O₂S m/z [M+H]⁺:275.1106; found: 275.1100.

tert-butyl 2-(pyridin-2-ylthio)acetate (9k)

Pale yellow oil; ¹H NMR (400 MHz, CDCl₃) δ 8.38 (ddd, J=4.9, 1.8, 0.9Hz, 1H), 7.48 (ddd, J=8.0, 7.4, 1.9 Hz, 1H), 7.22 (dt, J=8.1, 1.0 Hz,1H), 6.98 (ddd, J=7.3, 4.9, 1.0 Hz, 1H), 3.88 (s, 2H), 1.44 (s, 9H); ¹³CNMR (100 MHz, CDCl₃) δ 168.67, 157.33, 149.14, 135.98, 122.00, 119.65,81.68, 33.55, 27.90; IR: 2978.09, 1732.08, 1577.77, 1558.48, 1454.33,1415.75, 1369.46, 1300.02, 1257.59, 1145.72, 1122.57, 948.98, 852.54,759.95, 725.23 cm⁻¹; HRMS (ESI) calcd for C₁₁H₁₅NO₂S m/z [M+H]⁺:226.0902; found: 226.0892.

tert-butyl 2-(benzo[d]thiazol-2-ylthio)acetate (9l)

(see Qingping Zeng et al Benzoheterocyclecarboxaldehyde derivatives asIRE-1α inhibitors and their preparation and use for the treatment ofdiseases. WO2011127070A2 (2011)): Pale yellow oil; ¹H NMR (400 MHz,CDCl₃) 7.84 (d, J=8.1 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.41 (t, J=7.7Hz, 1H), 7.29 (t, J=7.6 Hz, 1H), 4.07 (s, 2H), 1.47 (s, 10H); ¹³C NMR(100 MHz, CDCl₃) δ 167.18, 165.09, 152.94, 135.47, 126.03, 124.34,121.57, 121.02, 82.57, 36.34, 27.91; IR: 2978.09, 2360.87, 1732.08,1462.04, 1427.32, 1392.61, 1369.46, 1303.88, 1145.72, 1002.98, 948.98,852.54, 756.10, 725.23, 489.92 cm⁻¹; HRMS (ESI) calcd for C₁₃H₁₅NO₂S₂m/z [M+H]⁺: 282.0622; found: 282.0618.

Synthesis of Other Sulfide Substrates (11a-g)

methyl 3-(benzhydrylthio)propanoate (11a)

(see Andrea Altieri et al. Sulfur-containing amide-based [2]rotaxanesand molecular shuttles. Chem. Sci. 2, 1922-1928 (2011)): Pale yellowoil; 94% yield; ¹H NMR (400 MHz, CDCl₃) δ 7.43 (d, J=7.5 Hz, 4H),7.38-7.28 (m, 4H), 7.28-7.18 (m, 2H), 5.21 (s, 1H), 3.68 (s, 3H), 2.69(dd, J=11.2, 4.0 Hz, 2H), 2.55 (dd, J=11.0, 3.9 Hz, 2H); ¹³C NMR (100MHz, CDCl₃) δ 172.22, 141.03, 128.55, 128.25, 127.24, 54.24, 51.72,34.09, 27.14; IR: 1728.22, 1600.92, 1492.90, 1446.61, 1435.04, 1357.89,1246.02, 1199.72, 1172.72, 1076.28, 1029.99, 979.84, 829.39, 748.38,702.09, 628.79, 586.36 cm⁻¹; HRMS (ESI) calcd for C₁₇H₁₈O₂S m/z [M+H]*:287.1106; found: 287.1106.

3-(benzhydrylthio)propanamide (11b)

(see Sidney Liang. Improved process for preparingbenzhydrylthioacetamide. WO2004075841A2 (2004); Surendra B. Bhatt et al.Improved process for the preparation of2-[(diphenylmethyl)thio]acetamide, intermediate for the preparation ofModafinil, from 2-[(diphenylmethyl)thio]acetic acid, alcohols andammonia.

WO2004075827A2 (2004)): White solid; mp: 111.0-112.2° C.; ¹H NMR (400MHz, CD₃OD) δ 7.42 (d, J=7.7 Hz, 4H), 7.28 (t, J=7.6 Hz, 4H), 7.20 (t,J=7.3 Hz, 2H), 5.35 (s, 1H), 3.03 (s, 2H); ¹³C NMR (100 MHz, CD₃OD) δ174.60, 142.00, 129.52, 129.36, 128.32, 55.30, 36.00; IR: 3360.00,1643.35, 1631.78, 1489.05, 1373.32, 1080.14, 921.97, 698.23 cm⁻¹; HRMS(ESI) calcd for C₁₅H₁₅NOS m/z [M+H]⁺: 258.0953; found: 258.0958.

2-(benzylthio)acetonitrile (11c)

(Gavin Chit Tsui, Quentin Glenadel, Chan Lau & Mark Lautens.Rhodium(I)-Catalyzed Addition of Arylboronic Acids to(Benzyl-/Arylsulfonyl)acetonitriles: Efficient Synthesis of(Z)-β-Sulfonylvinylamines and β-Keto Sulfones. Org. Lett. 13, 208-211(2011)): Pale yellow oil; ¹H NMR (400 MHz, CDCl₃) δ 7.30-7.23 (m, 4H),7.23-7.18 (m, 1H), 3.82 (s, 2H), 2.97 (s, 2H); ¹³C NMR (100 MHz, CDCl₃)δ 135.64, 129.00, 128.83, 127.78, 116.19, 35.98, 15.84; IR: 2245.14,1955.82, 1600.92, 1492.90, 1454.33, 1396.46, 1249.87, 1230.58, 1184.29,1072.42, 1029.99, 921.97, 894.97, 771.53, 725.23, 702.09, 675.09, 563.21cm⁻¹; HRMS (ESI) calcd for C₉H₉NS m/z [M+H]⁺:164.0534; found: 164.0548.

(E)-ethyl 4-(benzylthio)but-2-enoate (11d)

(Peter Schwenkkraus & Hans Hartwig Otto. Properties and reactions ofsubstituted 1,2-thiazetidine 1,1-dioxides: C-3 substituted β-sultams.Arch. Pharm. (Weinheim, Ger.) 326, 519-523 (1993); Charles M. Marson etal. Aromatic sulfide inhibitors of histone deacetylase based onarylsulfinyl-2,4-hexadienoic acid hydroxyamides. J. Med. Chem. 49,800-805 (2006)): Pale yellow oil; ¹H NMR (400 MHz, CDCl₃) δ 7.36-7.28(m, 4H), 7.27-7.22 (m, 1H), 6.95-6.77 (m, 1H), 5.84 (dt, J=15.5, 1.3 Hz,1H), 4.21 (q, J=7.1 Hz, 2H), 3.66 (s, 2H), 3.11 (dd, J=7.4, 1.3 Hz, 2H),1.31 (t, J=7.1 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 166.02, 143.39,137.54, 128.98, 128.56, 127.16, 123.09, 60.44, 35.22, 31.86, 14.21; IR:3028.24, 1712.79, 1651.07, 1492.90, 1454.33, 1369.46, 1315.45, 1265.30,1195.87, 1149.57, 1041.56, 979.84, 860.25, 748.38, 702.09 cm⁻¹; HRMS(ESI) calcd for C₁₃H₁₆O₂S m/z [M+H]⁺: 237.0949; found: 237.0951.

2-(benzylthio)-1-(p-tolyl)ethanone (11e)

(Hossein Loghmani-Khouzani, Mohammad R. Poorheravi, Majid M. M. Sadeghi,Lorenzo Caggiano & Richard F. W. Jackson. α-Fluorination ofβ-ketosulfones by Selectfluor F-TEDA-BF4. Tetrahedron 64, 7419-7425(2008)): To a suspension of K₂CO₃ (1.38 g, 10.0 mmol) and2-bromo-1-(p-tolyl)ethanone (959 mg, 4.5 mmol) in EtOH (15 mL), benzylmercaptan (587 μL, 5.0 mmol) was added dropwise. After vigorouslystirring for 5 h until the complete consumption of2-bromo-1-(p-tolyl)ethanone, EtOAc (50 mL) was added and the reactionmixture was diluted with water (10 mL). The aqueous layer was extractedwith EtOAc (2×50 mL) and the combined organic layer was washed by brineand dried by Na₂SO₄, filtered and concentrated. The crude residue wassubjected to purification by flash column chromatography (silica gel,hexanes: EtOAc, gradient from 50:1 to 20:1) to afford the product aspale yellow solid; mp: 69.4-70.5° C.; ¹H NMR (400 MHz, CDCl₃) δ 7.84 (d,J=8.2 Hz, 2H), 7.43-7.29 (m, 4H), 7.29-7.21 (m, 3H), 3.76 (s, 2H), 3.66(s, 2H), 2.42 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 194.13, 144.17,137.35, 132.89, 129.30, 129.23, 128.78, 128.47, 127.15, 36.08, 35.83,21.63; IR: 1670.35, 1604.77, 1492.90, 1454.33, 1419.61, 1280.73,1184.29, 1014.56, 837.11, 806.25, 771.53, 702.09, 551.64 cm⁻¹; HRMS(ESI) calcd for C₁₆H₁₆OS m/z [M+H]⁺: 257.1000; found: 257.1000.

2-(benzylthio)-1-(4-nitrophenyl)ethanone (11f)

(Hossein Loghmani-Khouzani, Mohammad R. Poorheravi, Majid M. M. Sadeghi,Lorenzo Caggiano & Richard F. W. Jackson. α-Fluorination ofβ-ketosulfones by Selectfluor F-TEDA-BF4. Tetrahedron 64, 7419-7425(2008)): Yellow solid; mp: 106.1-106.9° C.; ¹H NMR (400 MHz, CDCl₃) δ8.29 (d, J=8.8 Hz, 2H), 8.05 (d, J=8.8 Hz, 2H), 7.40-7.31 (m, 4H),7.30-7.25 (m, 1H), 3.73 (s, 2H), 3.68 (s, 2H); ¹³C NMR (100 MHz, CDCl₃)δ 192.44, 150.30, 139.89, 136.73, 129.73, 129.25, 128.59, 127.43,123.78, 36.09, 36.01; IR: 1678.07, 1600.92, 1519.91, 1415.75, 1350.17,1319.31, 1269.16, 856.39, 732.95, 705.95 cm⁻¹; HRMS (ESI) calcd forC₁₅H₁₃NO₃S m/z [M+H]⁺: 288.0694; found: 288.0687.

tert-butyl 2-((4-hydroxyphenyl)thio)acetate (11g)

(see Katsukiyo Miura, Naoki Fujisawa, Hiroshi Saito, Di Wang & AkiraHosomi. Synthetic Utility of Stannyl Enolates as Radical AlkylatingAgents1. Org. Lett. 3, 2591-2594 (2001)): Pale brown oil; ¹H NMR (400MHz, CDCl₃) δ 7.32 (d, J=8.5 Hz, 1H), 6.70 (d, J=8.5 Hz, 1H), 3.41 (s,2H), 1.41 (s, 4H); ¹³C NMR (100 MHz, CDCl₃) δ 170.17, 156.25, 134.40,124.20, 116.13, 82.22, 39.74, 27.86; IR: 3398.57, 1693.50, 1600.92,1581.63, 1496.76, 1431.18, 1369.46, 1311.59, 1265.30, 1168.86, 952.84,829.39, 640.37, 520.78 cm⁻¹; HRMS (ESI) calcd for C₁₂H₁₆O₃S m/z [M+H]⁺:241.0898; found: 241.0889.

4-(methylthio)benzaldehye (11h) may be made by analogy to the processesdescribed above, or may be obtained from commercial sources.

General Procedures

General Procedure 1: Sulfoxidation of Heterocyclic Sulfides UsingTungstate System

In a 4 mL sample vial, sulfides 2(0.2 mmol, 1.0 equiv), bisguanidiniumchloride (0.004 mmol, 0.02 equiv), silver tungstate oxide (0.004 mmol,0.02 equiv), sodium phosphate monobasic (0.02 mmol, 0.1 equiv) andsolvent were added. The temperature of the solution is then lowered tothe presupposed temperature. After stabilizing, H₂O₂ (1.05 equiv, 35%w/w) was injected in one portion into the system. The mixture wasstirred for 24 hours to 48 hours, and the termination of reaction wasmonitored by TLC. The resulting suspension was quenched by saturatedNa₂S₂O₃. EtOAc (0.5 mL×3) was used for extraction, and the organiclayers were combined and dried over anhydrous Na₂SO₄. The organicsolvent was removed in rotary evaporator (the water-bath temperature isunder 38° C.), and the residues were purified by chromatography onsilica gel to afford the desired products. R represents a chemical groupas provided by the sulfides/sulfoxides in Examples 2-3.

General Procedure 2: Sulfoxidation of Phenyl Sulfides Using TungstateSystem

In a 10 mL sample vial, sulfides 5 (0.2 mmol, 1.0 equiv), bisguanidiniumchloride (0.004 mmol, 0.02 equiv), silver tungstate oxide (0.004 mmol,0.02 equiv), ammonium phosphate monobasic (0.02 mmol, 0.1 equiv) and 8mL mixed solvent were added. The solvent mixture consisted of 4 mLdimethyl carbonate and 4 mL diethyl ether (diisopropyl ether in 5a).Then lower the solution to the presupposed temperature. Afterstabilizing, H₂O₂(1.05 equiv, 35% w/w) was injected in one portion intothe system. The mixture was stirred for 18 hours, and the termination ofreaction was monitored by TLC. The resulting suspension was quenched bysaturated Na₂S₂O₃. EtOAc (0.5 mL×3) was used for extraction, and theorganic layers were combined and dried over anhydrous Na₂SO₄. Theorganic solvent was removed in rotary evaporator (the water-bathtemperature is under 38° C.), and the residues were purified bychromatography on silica gel to afford the desired products. Rrepresents a chemical group as provided by the sulfides/sulfoxides inExample 5.

General Procedure 3: Sulfoxidation of Sulfides Using Molybdate System

A 10 mL round-bottomed flask was charged with a solution of methyl2-(benzhydrylthio)acetate 7a (54.4 mg, 0.2 mmol, 1.0 equiv.) andbis-guanidinium phase-transfer catalyst 1a (2.8 mg, 0.002 mmol, 0.01equiv.) in ^(i)Pr₂O (4 mL). Then Na₂MoO₄.2H₂O (1.2 mg, 0.005 mmol, 0.025equiv.) and KHSO₄ (13.6 mg, 0.1 mmol, 0.5 equiv.) were added. Thereaction mixture was stirred for 5 min in an ice-bath, and thenH₂O₂(35%, 17.2 μL, 0.2 mmol, 1.0 equiv) was added in one portion. Theresulting mixture was stirred vigorously at 0° C. and monitored by TLCuntil 7a was completely consumed. Purification by column chromatographyon silica gel using CH₂Cl₂: EtOAc 2:1 as the eluent gave the desiredsulfoxide 8a as a white solid. Minor changes in the amount of KHSO₄ andchoice of Molybdate salt (K₂MoO₄) and solvent (^(n)Bu₂O) should beconducted for some substrates in order to achieve slightly betterenantioselectivity.

Computational Studies

Calculations were performed using the Gaussian 09 software package(Frisch, M. J.; Trucks, G. W., et al., Gaussian 09, Gaussian, Inc.:Wallingford, Conn., USA, 2009). Two different models were considered.The small model (SM) was used to study the reactivity of differenttungstate species and does not contain the BG-1 structure. The othermultiscale model was used to study the reactivity of the completeion-pair structure by means of a two-layer ONIOM (QM:QM′) (Dapprich, S,et al., J. Mol. Struct. (Theochem) 1999, 462, 1-21) method. The B3LYPdensity functional theory (DFT) method and the semiempirical PM6(Stewart, J. J. P. J. Mol. Model. 2007, 13, 1173-1213) method were usedfor the QM and QM′ calculations, respectively.

For both models, DFT calculations were performed with the hybrid B3LYPfunctional [Becke, A. D., The Journal of Chemical Physics 1993, 98 (7),5648-5652; Lee, C.; Yang, W.; Parr, R. G., Physical Review B 1988, 37(2), 785-789; Vosko, S. H.; Wilk, L.; Nusair, M., Canadian Journal ofPhysics 1980, 58 (8), 1200-1211] and two basis sets, B1 and B2. B1 is acombination of the LANL2DZ effective core potential basis set (Hay, P.J.; Wadt, W. R., The Journal of Chemical Physics 1985, 82 (1), 299-310)for W and the 6-31g* basis set (Wiberg, K. B., Journal of ComputationalChemistry 1986, 7 (3), 379-379) for remaining atoms, which was used forgeometry optimization calculations. Vibrational analysis were done forB3LYP/B1-derived stationary points to confirm their nature and to obtainzero-point energy (ZPE) corrections. To improve the accuracy ofenergies, single-point energy calculations were performed on theB3LYP/B1 geometries with basis set B2, which is the combination of SDDeffective core potential basis set (Dolg, M.; Wedig, U.; Stoll, H.;Preuss, H., The Journal of Chemical Physics 1987, 86 (2), 866-872) for Wand 6-311+g(df,p) on other atoms. Solvent effects on the reactions wereincluded in geometry optimizations, using a self-consistent reactionfield (SCRF) method called IEFPCM (Tomasi, J.; Mennucci, B.; Cammi, R.,Chemical Reviews 2005, 105 (8), 2999-3094) as implemented in Gaussian09. Visualization of resulting structures was generated using UCSFChimera, unless stated otherwise (Pettersen, E. F.; Goddard, T. D.;Huang, C. C.; Couch, G. S.; Greenblatt, D. M.; Meng, E. C.; Ferrin, T.E. J. Comput. Chem. 2004, 25 (13), 1605-1612).

EXAMPLES Example 1: Synthetic Protocol of Isolated Complex (R,R)-1c

To a solution of Na₂MoO₄.2H₂O (24.1 mg, 0.1 mmol, 2.5 mol %) dissolvedin 1M H₂SO₄(1 mL, 0.25 equiv.), 35% H₂O₂(345 μL, 4.0 mmol, 1.0 equiv.)was added dropwise to give a yellow solution at room temperature. Thenthe above solution was added dropwise to a solution of (R,R)-1b (56.4mg, 0.04 mmol, 1 mol %) in Et₂O (2 mL). After vigorously stirred for 15minutes, a pale-yellow precipitate was formed in the Et₂O layer. Afterfurther stirring for 2h and removal of Et₂O by evaporation, 4 mLdeionized water was added and the resulting heterogeneous mixture wassubmitted to ultrasound for 1 minute. Then the pale-yellow solid wasfiltered off and washed with deionized water (40 mL). After dried withconcentrated H₂SO₄ by using vacuum oil pump, (R,R)-1c was obtained as apale-yellow powder (65.5 mg, 91% yield) and its structure wascharacterized and determined by X-ray single crystal diffraction.Increase of the amount of Na₂MoO₄.2H₂O to 0.1 equivalent or replacementof 1M H₂SO₄ by 0.5 equivalent of solid KHSO₄ all led to the formation ofidentical complex (R,R)-1c, which is confirmed by X-ray diffractionanalysis. FIG. 14 provides a general synthetic route towards (R,R)-1c.¹H NMR (400 MHz, DMF-d₇) δ 7.45-7.38 (m, 12H), 7.37 (s, 4H), 7.21 (dd,J=6.3, 2.7 Hz, 8H), 7.07 (d, J=1.4 Hz, 8H), 5.22 (d, J=14.5 Hz, 4H),4.89 (d, J=14.5 Hz, 4H), 4.57 (s, 4H), 4.55 (t, J=12.7 Hz, 8H), 1.17 (s,72H); ¹³C NMR (100 MHz, DMF-d₇) δ 164.19, 152.34, 139.37, 133.86,130.54, 130.01, 127.74, 124.64, 123.49, 70.74, 54.40, 50.25, 35.63,31.94; ⁹⁵Mo NMR (26 MHz, DMF-d₇) δ −199.29; IR: 2962.66, 1597.06,1527.62, 1477.47, 1454.33, 1361.74, 1284.59, 1249.87, 1199.72, 1157.29,1114.86, 1076.28, 1049.27, 1018.41, 972.12 (Mo═O), 937.40, 918.12,871.82 (O—O), 759.55, 702.09, 663.51 (Mo—(O₂)), 590.22 (Mo—(O₂)). FIG.16 provides the Infrared spectrum of (R,R)-1c.

A single crystal structure of (R,R)-1c is provided in FIG. 8. Crystaldata for (R,R)-1c: [C₉₄H₁₂₄Mo₂N₆O₁₄S.2C₃H₇NO.C₄H₁₀O], M=2006.24,monoclinic, P 1 21 1, a=9.9398(8), b=30.471(3), c=17.5604(15) Å, α=90,β=97.837(3)°, γ=90°, V=5268.9(8) Å³, Z=2, ρ_(calcd)=1.265 g/cm³,μ(CuKα)=0.324 mm⁻¹, T=103(2) K, Wavelength=0.71073 Å, yellow plate.Bruker X8 CCD X-ray diffractionmeter; 20085 independent measuredreflections, F² refinement, R₁(obs)=0.0715, wR₂(all)=0.1585, 12673independent observed absorption-corrected reflections, 1426 parameters.Crystallographic data for this paper have been deposited at theCambridge Crystallographic Data Centre under deposition number CCDC1456990.

Example 2: Optimization of Reaction Conditions for Tungstate-CatalyzedOxidation

TABLE 1 Optimization of the reaction conditions.

entry BG M_(x)(WO₄)_(y) Additive Solvent yield (%)^(b) ee (%)^(c)  1^(d) BG-1 — — Et₂O N.R. N.A.  2 BG-1 Na₂WO₄ — Et₂O 20 −5  3 BG-1Na₂WO₄ NaH₂PO₄ Et₂O 36 20  4 BG-1 K₂WO₄ NaH₂PO₄ Et₂O 18 −2  5 BG-1(NH₄)₂WO₄ NaH₂PO₄ Et₂O 48 42  6 BG-1 Ag₂WO₄ LiH₂PO₄ Et₂O 70 90  7 BG-1Ag₂WO₄ NaH₂PO₄ Et₂O 83 88  8 ent-BG-1 Ag₂WO₄ NaH₂PO₄ Et₂O 90 −89   9BG-1 Ag₂WO₄ KH₂PO₄ Et₂O 83 84 10 BG-1 Ag₂WO₄ NH₄H₂PO₄ Et₂O 82 82 11 BG-1Ag₂WO₄ NaHSO₄ Et₂O 52 80 12 BG-1 Ag₂WO₄ NaH₂PO₄ Tol 60 74 13 BG-1 Ag₂WO₄NaH₂PO₄ DCM 68 20 14 BG-1 Ag₂WO₄ ^(e) NaH₂PO₄ Et₂O 55 50 15 BG-1 Ag₂WO₄^(e) NaH₂PO₄ i-Pr₂O 96 92 16 BG-2 Ag₂WO₄ ^(e) NaH₂PO₄ i-Pr₂O 65 63 17BG-3 Ag₂WO₄ ^(e) NaH₂PO₄ i-Pr₂O 63 50 18 BG-4 Ag₂WO₄ ^(e) NaH₂PO₄ i-Pr₂O52 32 19 BG-5 Ag₂WO₄ ^(e) NaH₂PO₄ i-Pr₂O 84  8 20 BG-1 — NaH₂PO₄ i-Pr₂O19 N.A. BG1: R = 3,5-(tBu)₂PhCH₂ BG2: R = 4-MeO-3,5-(tBu)₂PhCH₂ BG3: R =2-fluoro-3,5-(tBu)₂PhCH₂ BG4: R = 2-chloro-3,5-(tBu)₂PhCH₂ BG5: R =2-bromo-3,5-(tBu)₂PhCH₂ Unless otherwise stated, reaction was performedwith 2a (0.05 mmol), H₂O₂ (0.0525 mmol, 1.05 equiv, 35% w/w), BG (0.001mmol, 2.0 mol %), M_(x)(WO₄)_(y) (0.0025 mmol, 5.0 mol %), 1.0 mL Et₂Oat 0° C. ^(b)Yield of isolated product. ^(c)Determined by HPLC analysison a chiral stationary phase. ^(d)No reaction was also observed at roomtemperature. ^(e)2.0 mol % of Ag₂WO₄ was used.

As set out in Table 1, reaction conditions for tungstate-catalyzedsulfoxidation were optimized with variance on the identity and/or amountof, for example, the organic cation, the tungstate-containing salt, thephosphate-containing additive and the solvent used. Sulfoxide product2′a was made from its reduced form via General Procedure 1, unlessotherwise stated.

Benzimidazole-derived benzyl sulfide 2a was chosen as the modelsubstrate. In the presence of 2.0 mol % of bisguanidinium BG1 with Et₂Oas solvent (Table 1, entry 1), no reaction was found when only H₂O₂ wasused. This indicates that BG1 alone cannot catalyze the reaction. When5.0 mol % of Na₂WO₄ was added, the reaction gave sulfoxide 2′a in pooryield and low enantioselectivity (entry 2). It is only when 10 mol %NaH₂PO₄ was added, the yield of sulfoxide 2′a improved significantly to36% and its ee value improved to 20% (entry 3). When Na₂HPO₄ and Na₃PO₄were used instead, the reactions were inhibited.

Next, a range of commercially available tungstate salts, such as K₂WO₄,(NH₄)₂WO₄ and Ag₂WO₄ were evaluated (entries 4-6). Sulfoxide 2′a wasobtained in 83% yield with 88% ee value when Ag₂WO₄ was used (entry 7).When the catalyst loading of Ag₂WO₄ was decreased to 2.0 mol %, it isnecessary to change the solvent to diisopropyl ether to provide the bestresults (entry 15). Other bisguanidiniums BG2-5 featuring differentbenzyl groups were unable to improve the results obtained with BG1(entries 16-19). It was also confirmed that the use of NaH₂PO₄ in theabsence of Ag₂WO₄ did not promote the sulfoxidation reaction (entry 20).Characterization data of 2′a is provided in Example 3.

Example 3: Enantioselective Sulfoxidation of Heterocyclic Sulfides andCharacterization of Sulfoxide Products

The substrate scope of benzimidazole-derived sulfides was examined(Scheme 1, 2′a-2′i).

The benzimidazole group does not seem to act as a ligand and inhibit thereaction. Both electron donating and electron withdrawing substitutionson the benzyl group worked well, affording the correspondingsulfoxidation products in good to excellent yields with good levels ofenantioselectivities. The oxidation ability of the catalyst is able tooverride even highly electron withdrawing group such aspentafluorobenzyl (Scheme 1, 2′g). Besides benzyl groups, simple alkylgroups or esters are also tolerated in this reaction (2′h-l). Otherheterocyclic systems such as benzothiazole (2′m-r), pyridine (2's-t) andthiophene (2′u) also worked well providing products with excellent eevalues. However, thiophene heterocyclic sulfides gave lower yields withsignificant amount of sulfone detected.

The reaction was scaled up to gram scale (3.5 mmol) to give 2′q in 91%yield and 92% ee.

Determination of the Absolute Configuration by X-Ray Crystallography.

FIGS. 9A-E depict ORTEP diagrams showing X-ray crystal structure ofproducts (S)-2′a, (S)-2′b, (S)-2′c, (S)-2′q and (S)-2′m respectively

The following sulfoxide products were made from their reduced forms(2a-2u) via General Procedure 1, unless otherwise stated.

(S)-2-(benzylsulfinyl)-1-methyl-1H-benzo[d]imidazole (2′a)

96% yield; white solid; ¹H NMR (400 MHz, CDCl₃) δ 7.87-7.82 (m, 1H),7.38-7.35 (m, 2H), 7.32-7.26 (m, 2H), 7.21 (td, J=10.4, 4.7 Hz, 2H),7.03 (dd, 2H), 4.64 (d, J=12.9 Hz, 1H), 4.50 (d, J=12.9 Hz, 1H), 3.45(s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 150.01, 141.54, 136.47, 130.61,128.89, 128.77, 124.68, 123.77, 120.59, 109.83, 60.96, 29.97; HRMS (ESI)calcd for C₁₅H₁₄N₂OS m/z [M+H]⁺: 271.0905; found: 271.0904; [α]_(D)²²=−29.16 (c 3.8, CH₂Cl₂); HPLC analysis: Chiralcel OJ-H (Hex/IPA=70/30,1.0 mL/min, 254 nm, 22° C.), 17.1, 29.0 (major) min, 92% ee.

(S)-1-methyl-2-((4-methylbenzyl)sulfinyl)-1H-benzo[d]imidazole (2′b)

94% yield; white solid; ¹H NMR (400 MHz, CDCl₃) δ 7.89-7.78 (m, 1H),7.38-7.33 (m, 2H), 7.32-7.27 (m, 1H), 7.03 (d, J=7.9 Hz, 2H), 6.93 (d,J=8.0 Hz, 2H), 4.62 (d, J=12.9 Hz, 1H), 4.45 (d, J=12.9 Hz, 1H), 3.49(s, 3H), 2.30 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 150.38, 142.01,138.80, 136.58, 130.50, 129.45, 125.73, 124.51, 123.53, 120.78, 109.78,60.62, 30.03, 21.27; HRMS (ESI) calcd for C₁₆H₁₆N₂OS m/z [M+H]⁺:285.1062; found: 285.1056; [α]_(D) ²²=−29.41 (c 2.2, CH₂Cl₂); HPLCanalysis: Daicel Corporation IB3 (Hex/IPA=70/30, 1.0 mL/min, 254 nm, 22°C.), 8.4, 15.4 (major) min, 94% ee.

(S)-2-((4-chlorobenzyl)sulfinyl)-1-methyl-1H-benzo[d]imidazole (2′c)

81% yield; white solid; ¹H NMR (400 MHz, CDCl₃) δ 7.82 (dd, J=8.0, 6.6Hz, 1H), 7.36 (qd, J=12.8, 8.0 Hz, 3H), 7.22 (d, J=8.3 Hz, 2H), 7.01 (d,J=8.3 Hz, 2H), 4.63 (d, J=13.0 Hz, 1H), 4.47 (d, J=13.0 Hz, 1H), 3.59(s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 149.73, 141.95, 136.67, 135.11,131.96, 128.97, 127.55, 124.75, 123.74, 120.80, 109.88, 59.90, 30.23;HRMS (ESI) calcd for C₁₅H₁₃ClN₂OS m/z [M+H]*: 305.0515; found: 305.0518;[α]_(D) ²²=−41.21 (c 3.2, CH₂Cl₂); HPLC analysis: Daicel Corporation IB3(Hex/IPA=70/30, 1.0 mL/min, 254 nm, 22° C.), 9.3, 30.4 (major) min, 97%ee.

(S)-2-((4-fluorobenzyl)sulfinyl)-1-methyl-1H-benzo[d]imidazole (2′d)

78% yield; white solid; ¹H NMR (400 MHz, CDCl₃) δ 7.87-7.78 (m, 1H),7.43-7.29 (m, 3H), 7.04 (dd, J=8.4, 5.5 Hz, 2H), 6.91 (t, J=8.6 Hz, 2H),4.60 (dd, J=30.8, 13.2 Hz, 2H), 3.56 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ164.47, 162.00, 149.54, 140.37, 136.17, 132.38, 132.30, 125.06, 124.75,124.71, 124.30, 120.10, 115.91, 115.70, 110.00, 59.95, 30.23; HRMS (ESI)calcd for C₁₅H₁₃FN₂OS m/z [M+H]⁺: 289.0811; found: 289.0808; [α]_(D)²²=−33.38 (c 4.3, CH₂Cl₂); HPLC analysis: Daicel Corporation IB3(Hex/IPA=70/30, 1.0 mL/min, 254 nm, 22° C.), 8.9, 29.7 (major) min, 88%ee.

(S)-1-methyl-2-((4-nitrobenzyl)sulfinyl)-1H-benzo[d]imidazole (2′e)

74% yield; yellow solid; ¹H NMR (400 MHz, CDCl₃) δ 8.10 (d, J=8.3 Hz,1H), 7.82 (d, J=7.4 Hz, 1H), 7.60-7.27 (m, 2H), 4.72 (dd, J=42.3, 12.9Hz, 1H), 3.69 (s, 1H); ¹³C NMR (101 MHz, CDCl₃) δ 149.17, 148.18,141.87, 136.73, 136.60, 131.66, 124.99, 123.91, 123.72, 120.84, 109.96,59.48, 30.46; HRMS (ESI) calcd for C₁₅H₁₃N₃O₃S m/z [M+H]⁺: 316.0756;found: 316.0761; [α]_(D) ²²=−213.88 (c 2.3, CH₂Cl₂); HPLC analysis:Daicel Corporation IA3 (Hex/IPA=70/30, 1.0 mL/min, 254 nm, 22° C.),14.3, 25.0 (major) min, 88% ee.

(S)-1-methyl-2-((naphthalen-2-ylmethyl)sulfinyl)-1H-benzo[d]imidazole(2′f)

95% yield; white solid; ¹H NMR (400 MHz, CDCl₃) δ 7.92-7.85 (m, 1H),7.77 (d, J=7.8 Hz, 1H), 7.66 (d, J=8.4 Hz, 1H), 7.62 (dd, 1H), 7.58 (s,1H), 7.50-7.34 (m, 4H), 7.23-7.17 (m, 1H), 7.06 (dd, J=8.4, 1.7 Hz, 1H),4.82 (d, J=12.9 Hz, 1H), 4.69 (d, J=12.9 Hz, 1H), 3.35 (s, 3H); ¹³C NMR(101 MHz, CDCl₃) δ 149.98, 141.18, 136.34, 133.09, 133.08, 130.23,128.35, 127.90, 127.65, 127.51, 126.67, 126.54, 126.18, 124.70, 123.83,120.40, 109.79, 61.21, 30.00; HRMS (ESI) calcd for C₁₉H₁₆N₂OS m/z[M+H]*: 321.1062; found: 321.1062; [α]_(D) ²²=−222.58 (c 2.2, CH₂Cl₂);HPLC analysis: Daicel Corporation IB3 (Hex/IPA=70/30, 1.0 mL/min, 254nm, 22° C.), 10.7, 38.0 (major) min, 99% ee.

(S)-1-methyl-2-(((perfluorophenyl)methyl)sulfinyl)-1H-benzo[d]imidazole(2′g)

84% yield; white solid; ¹H NMR (400 MHz, CDCl₃) δ 7.80 (d, J=8.1 Hz,1H), 7.48-7.33 (m, 3H), 4.88 (d, J=13.2 Hz, 1H), 4.71 (d, J=13.1 Hz,1H), 4.09 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 149.60, 141.96, 137.04,125.30, 123.95, 121.11, 109.99, 47.47, 30.92; HRMS (ESI) calcd forC₁₅H₉F₅N₂OS m/z [M+H]*: 361.0434; found: 361.0435; [α]_(D) ¹²=−141.82 (c2.2, CH₂Cl₂); HPLC analysis: Daicel Corporation 1B3 (Hex/IPA=70/30, 1.0mL/min, 254 nm, 22° C.), 10.2, 15.6 (major) min, 92% ee.

(S)-2-((2-(1,3-dioxolan-2-yl)ethyl)sulfinyl)-1-methyl-1H-benzo[d]imidazole(2′h)

72% yield; colorless oil; ¹H NMR (400 MHz, CDCl₃) δ 7.81 (d, J=7.9 Hz,1H), 7.45-7.36 (m, 2H), 7.34 (ddd, J=8.3, 6.6, 1.8 Hz, 1H), 5.04 (t,J=3.9 Hz, 1H), 4.11 (s, 3H), 4.01-3.92 (m, 2H), 3.89-3.80 (m, 2H), 3.59(ddd, J=8.3, 6.8, 1.8 Hz, 2H), 2.28 (dddd, J=14.8, 8.0, 6.9, 4.0 Hz,1H), 2.14 (dddd, J=9.9, 7.5, 6.6, 3.5 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃)δ 151.13, 141.62, 136.73, 124.84, 123.71, 120.85, 109.98, 102.46, 65.26,47.86, 31.01, 26.58; HRMS (ESI) calcd for C₁₃H₁₆N₂O₃S m/z [M+H]⁺:281.0960; found: 281.0959; [α]_(D) ²²=+8.45 (c 0.9, CHCl₃); HPLCanalysis: Daicel Corporation IB3 (Hex/IPA=70/30, 1.0 mL/min, 254 nm, 22°C.), 15.1, 19.3 (major) min, 95% ee.

(S)-6-((I-methyl-1H-benzo[d]imidazol-2-yl)sulfinyl)hexanenitrile (2′i)

71% yield; colorless oil; ¹H NMR (400 MHz, CDCl₃) δ 7.84-7.78 (m, 1H),7.47-7.39 (m, 2H), 7.37 (ddd, 1H), 4.14 (s, 3H), 3.57 (ddd, J=13.2, 9.4,5.6 Hz, 1H), 3.45 (ddd, J=13.2, 9.5, 6.3 Hz, 1H), 2.36 (t, J=6.8 Hz,2H), 2.05-1.81 (m, 2H), 1.79-1.63 (m, 4H); ¹³C NMR (101 MHz, CDCl₃) δ150.80, 141.27, 136.74, 125.02, 123.96, 120.68, 119.40, 110.09, 52.84,31.13, 27.71, 25.06, 21.66, 17.05; HRMS (ESI) calcd for C₁₄H₁₇N₃OS m/z[M+Na]⁺: 298.0990; found: 298.0996; [α]_(D) ²²=+7.71 (c 0.7, CHCl₃);HPLC analysis: Daicel Corporation IB3 (Hex/IPA=70/30, 1.0 mL/min, 254nm, 22° C.), 24.6, 41.0 (major) min, 82% ee.

(S)-methyl-2-((1-methyl-1H-benzo[d]imidazol-2-yl)sulfinyl)acetate (2′j)

85% yield; white solid; ¹H NMR (400 MHz, CDCl₃) δ 7.84-7.77 (m, 1H),7.46-7.39 (m, 2H), 7.36 (ddd, J=8.3, 6.4, 2.0 Hz, 1H), 4.69 (d, J=15.1Hz, 1H), 4.44 (d, J=15.1 Hz, 1H), 4.11 (s, 3H), 3.74 (s, 3H); ¹³C NMR(101 MHz, CDCl₃) δ 165.45, 165.43, 150.83, 141.38, 136.67, 125.25,125.18, 123.97, 121.01, 120.92, 110.20, 57.21, 53.12, 31.04; HRMS (ESI)calcd for C₁₁H₁₂N₂O₃S m/z [M+H]⁺: 253.0647; found: 253.0645; [α]_(D)²²=+5.25 (c 1.2, CH₂Cl₂); HPLC analysis: Daicel Corporation IB3(Hex/IPA=70/30, 1.0 mL/min, 254 nm, 22° C.), 15.6, 22.0 (major) min, 89%ee.

(S)-ethyl-2-((1-methyl-1H-benzo[d]imidazol-2-yl)sulfinyl)acetate (2′k)

92% yield; white solid; ¹H NMR (400 MHz, CDCl₃) δ 7.80 (d, J=8.0 Hz,1H), 7.46-7.38 (m, 2H), 7.35 (ddd, J=8.2, 6.5, 1.9 Hz, 1H), 4.65 (t,J=14.3 Hz, 1H), 4.41 (d, J=15.0 Hz, 1H), 4.18 (q, J=7.1 Hz, 2H), 4.10(s, 3H), 1.21 (t, J=7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 164.92,150.95, 141.46, 136.66, 125.11, 123.89, 120.93, 110.16, 62.39, 57.45,31.01, 14.05; HRMS (ESI) calcd for C₁₂H₁₄N₂O₃S m/z [M+H]⁺: 267.0803;found: 267.0807; [α]_(D) ²²=+4.62 (c 1.2, CH₂Cl₂); HPLC analysis: DaicelCorporation 1B3 (Hex/IPA=70/30, 1.0 mL/min, 254 nm, 22° C.), 11.4, 16.6(major) min, 90% ee.

(S)-tert-butyl-2-((1-methyl-1H-benzo[d]imidazol-2-yl)sulfinyl)acetate(2′l)

86% yield; white solid; ¹H NMR (400 MHz, CDCl₃) δ 7.83-7.75 (m, 1H),7.46-7.38 (m, 2H), 7.35 (ddd, J=8.3, 6.5, 1.9 Hz, 1H), 4.57 (d, J=14.8Hz, 1H), 4.34 (d, J=14.8 Hz, 1H), 4.11 (s, 3H), 1.39 (s, 9H); ¹³C NMR(101 MHz, CDCl₃) δ 163.93, 151.09, 141.45, 136.64, 125.06, 123.86,120.89, 110.13, 83.86, 58.46, 31.01, 27.97; HRMS (ESI) calcd forC₁₄H₁₈N₂O₃S m/z [M+Na]⁺: 317.0936; found: 317.0937; [α]_(D) ²²=+13.78 (c1.1, CHCl₃); HPLC analysis: Daicel Corporation IB3 (Hex/IPA=70/30, 1.0mL/min, 254 nm, 22° C.), 7.3, 8.6 (major) min, 80% ee.

(S)-2-(benzylsulfinyl)benzo[d]thiazole (2′m)

78% yield; white solid; ¹H NMR (400 MHz, CDCl₃) δ 8.09 (d, J=8.2 Hz,1H), 7.93 (d, J=8.1 Hz, 1H), 7.57 (t, J=7.3 Hz, 1H), 7.47 (t, J=7.6 Hz,1H), 7.34-7.23 (m, 3H), 7.17 (d, J=6.8 Hz, 2H), 4.51 (d, J=13.1 Hz, 1H),4.33 (d, J=13.1 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ 176.99, 153.74,136.04, 130.47, 128.75, 128.71, 128.39, 126.93, 126.16, 123.93, 122.26,118.61, 62.85; HRMS (ESI) calcd for C₁₄H₁₁NOS₂ m/z [M+H]⁺: 274.0360;found: 274.0356; [α]_(D) ¹²=−47.99 (c 3.3, CH₂Cl₂); HPLC analysis:Chiralcel OD-H (Hex/IPA=90/10, 1.0 mL/min, 254 nm, 22° C.), 13.4(major), 16.4 min, 93% ee.

(S)-2-((4-methylbenzyl)sulfinyl)benzo[d]thiazole (2′n)

70% yield; white solid; ¹H NMR (400 MHz, CDCl₃) δ 8.10 (d, J=8.2 Hz,1H), 7.95 (d, J=8.0 Hz, 1H), 7.57 (ddd, J=8.3, 7.3, 1.2 Hz, 1H), 7.48(ddd, 1H), 7.15-7.01 (m, 4H), 4.48 (d, J=13.1 Hz, 1H), 4.31 (d, J=13.1Hz, 1H), 2.31 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 177.27, 153.84,138.80, 136.13, 130.46, 129.56, 127.00, 126.22, 125.37, 124.00, 122.37,62.82, 21.32; HRMS (ESI) calcd for C₁₅H₁₃NOS₂ m/z [M+Na]⁺: 310.0336;found: 310.0333; [α]_(D) ²²=−74.52 (c 1.6, CH₂Cl₂); HPLC analysis:Chiralcel OD-H (Hex/IPA=90/10, 1.0 mL/min, 254 nm, 22° C.), 12.4(major), 15.9 min, 90% ee.

(S)-2-((3-methoxybenzyl)sulfinyl)benzo[d]thiazole (2′o)

94% yield; white solid; ¹H NMR (400 MHz, CDCl₃) δ 8.10 (d, J=8.2 Hz,1H), 7.95 (d, J=8.1 Hz, 1H), 7.57 (ddd, 1H), 7.48 (ddd, 1H), 7.18 (t,J=7.9 Hz, 1H), 6.84 (dd, J=8.2, 2.3 Hz, 1H), 6.79 (d, J=7.5 Hz, 1H),6.66 (d, J=1.8 Hz, 1H), 4.48 (d, J=13.1 Hz, 1H), 4.30 (d, J=13.1 Hz,1H), 3.60 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 177.19, 159.82, 153.84,136.17, 129.86, 129.82, 127.05, 126.29, 124.00, 122.95, 122.39, 115.26,115.21, 63.17, 55.18, 25.48; HRMS (ESI) calcd for C₁₅H₁₃NO₂S₂ m/z[M+H]⁺: 304.0466; found: 304.0467; [α]_(D) ²²=−59.08 (c 3.1, CH₂Cl₂);HPLC analysis: Daicel Corporation IB3 (Hex/IPA=70/30, 1.0 mL/min, 254nm, 22° C.), 7.3 (major), 7.6 min, 91% ee.

(S)-2-((3,5-dimethoxybenzyl)sulfinyl)benzo[d]thiazole (2′p)

86% yield; white solid; ¹H NMR (400 MHz, CDCl₃) δ 8.09 (d, J=8.2 Hz,1H), 7.96 (d, J=8.1 Hz, 1H), 7.56 (ddd, 1H), 7.48 (ddd, J=11.2, 4.1 Hz,1H), 6.41-6.35 (m, 1H), 6.31 (d, J=2.2 Hz, 2H), 4.43 (d, J=13.0 Hz, 1H),4.26 (d, J=13.0 Hz, 1H), 3.60 (s, 6H); ¹³C NMR (101 MHz, CDCl₃) δ177.30, 160.97, 153.85, 136.20, 130.55, 127.07, 126.32, 124.00, 122.41,108.22, 101.57, 63.57, 55.35; HRMS (ESI) calcd for C₁₆H₁₅NO₃S₂ m/z[M+H]⁺: 334.0572; found: 334.0574; [α]_(D) ²²f=−166.21 (c 3.1, CHCl₃);HPLC analysis: Chiralcel OD-H (Hex/IPA=90/10, 0.5 mL/min, 254 nm, 22°C.), 37.8 (major), 42.4 min, 92% ee.

(S)-2-((naphthalen-2-ylmethyl)sulfinyl)benzo[d]thiazole (2′q)

85% yield; white solid; ¹H NMR (400 MHz, CDCl₃) δ 8.12 (d, J=8.2 Hz,1H), 7.90 (d, J=8.1 Hz, 1H), 7.83-7.76 (m, 1H), 7.72 (dd, J=8.7, 4.9 Hz,3H), 7.58 (ddd, 1H), 7.51-7.41 (m, 3H), 7.25 (dd, J=8.5, 1.7 Hz, 1H),4.68 (d, J=13.1 Hz, 1H), 4.50 (d, J=13.1 Hz, 1H); ¹³C NMR (101 MHz,CDCl₃) δ 177.12, 153.87, 136.14, 133.27, 133.26, 130.36, 128.59, 128.10,127.79, 127.58, 127.05, 126.66, 126.51, 126.26, 124.02, 122.38, 63.41.;HRMS (ESI) calcd for C₁₈H₁₃NOS₂ m/z [M+H]⁺: 324.0517; found: 324.0523;[α]_(D) ²²=−78.47 (c 2.2, CH₂Cl₂); HPLC analysis: Chiralcel AS-H(Hex/IPA=90/10, 1.0 mL/min, 254 nm, 22° C.), 36.1, 43.4 (major) min, 91%ee.

(S)-2-(propylsulfinyl)benzo[d]thiazole (2′r)

70% yield; colorless oil; ¹H NMR (400 MHz, CDCl₃) δ 8.04 (d, J=8.2 Hz,1H), 7.98 (d, J=8.0 Hz, 1H), 7.54 (t, J=7.7 Hz, 1H), 7.47 (t, J=7.6 Hz,1H), 3.26-3.11 (m, 2H), 1.99 (tq, J=14.8, 7.4 Hz, 1H), 1.76 (tq, 1H),1.08 (t, J=7.4 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 177.86, 153.99,136.02, 126.99, 126.21, 123.97, 122.36, 116.21, 58.61, 15.53, 13.24;HRMS (ESI) calcd for C₁₀H₁₁NOS₂ m/z [M+Na]⁺: 248.0180; found: 248.0176;[α]_(D) ²²=−1.15 (c 2.0, CH₂Cl₂); HPLC analysis: Chiralcel OB-H(Hex/IPA=90/10, 1.0 mL/min, 254 nm, 22° C.), 12.3 (major), 14.5 min, 91%ee.

(S)-2-(benzylsulfinyl)pyridine (2's)

76% yield; white solid; ¹H NMR (400 MHz, CDCl₃) δ 8.69 (d, J=4.3 Hz,1H), 7.80 (td, J=7.7, 1.7 Hz, 1H), 7.63 (d, J=7.9 Hz, 1H), 7.37 (ddd,J=7.6, 4.7, 1.1 Hz, 1H), 7.31-7.21 (m, 3H), 7.04 (dd, J=7.7, 1.6 Hz,2H), 4.40 (d, J=13.1 Hz, 1H), 4.10 (d, J=13.1 Hz, 1H); ¹³C NMR (101 MHz,CDCl₃) δ 163.64, 149.11, 137.86, 130.27, 129.31, 128.31, 128.17, 124.67,120.73, 59.97; HRMS (ESI) calcd for C₁₂H₁₁NOS m/z [M+H]⁺: 218.0640;found: 218.0639; [α]_(D) ²²=−205.63 (c 2.6, CHCl₃); HPLC analysis:Chiralcel OD-H (Hex/IPA=90/10, 1.0 mL/min, 254 nm, 22° C.), 17.7(major), 21.9 min, 80% ee.

(S)-2-((4-methylbenzyl)sulfinyl)pyridine (2′t)

96% yield; white solid; ¹H NMR (400 MHz, CDCl₃) δ 8.71-8.51 (m, 1H),7.78 (td, J=7.7, 1.7 Hz, 1H), 7.62 (dt, J=7.9, 0.9 Hz, 1H), 7.33 (ddd,J=7.6, 4.7, 1.2 Hz, 1H), 7.02 (d, J=7.8 Hz, 2H), 6.89 (d, J=8.0 Hz, 2H),4.33 (d, J=13.1 Hz, 1H), 4.03 (d, J=13.1 Hz, 1H), 2.28 (s, 3H); ¹³C NMR(101 MHz, CDCl₃) δ 163.90, 149.26, 138.08, 137.84, 130.25, 129.14,126.26, 124.67, 120.77, 59.87, 21.24; HRMS (ESI) calcd for C₁₃H₁₃NOS m/z[M+Na]⁺: 254.0616; found: 254.0620; [α]_(D) ²²=−253.06 (c 3.4, CHCl₃);HPLC analysis: Chiralcel OB-H (Hex/IPA=90/10, 0.5 mL/min, 254 nm, 22°C.), 21.7 (major), 25.5 min, 85% ee.

(S)-2-(benzylsulfinyl)thiophene (2′u)

53% yield; white solid; ¹H NMR (400 MHz, CDCl₃) δ 7.62 (d, J=4.9 Hz,1H), 7.32-7.24 (m, 3H), 7.13 (t, J=4.1 Hz, 1H), 7.08 (dd, J=7.2, 1.9 Hz,2H), 7.05-6.98 (m, 1H), 4.36 (d, J=12.4 Hz, 1H), 4.15 (d, J=12.4 Hz,1H); ¹³C NMR (101 MHz, CDCl₃) δ 144.93, 131.19, 130.33, 129.89, 129.34,128.80, 128.58, 127.28, 65.14; HRMS (ESI) calcd for C₁₁H₁₀OS₂ m/z[M+H]⁺: 245.0071; found: 245.0071; [α]_(D) ²²=+73.96 (c 1.0, CHCl₃);HPLC analysis: Chiralcel OD-H (Hex/IPA=90/10, 1.0 mL/min, 254 nm, 22°C.), 18.5, 25.0 (major) min, 95% ee.

Example 4: Enantioselective Synthesis and Characterization of(S)-Lansoprazole

The established strategy was also successfully applied to thepreparation of (S)-Lansoprazole, a commercial proton-pump inhibitor.

Synthetic Protocol:

In a 25 mL round-bottomed flask, sulfides 3 (0.2 mmol, 1.0 equiv),bisguanidinium chloride (0.004 mmol, 0.02 equiv), silver tungstate oxide(0.004 mmol, 0.02 equiv), ammonium phosphate monobasic (0.02 mmol, 0.1equiv) and 8 mL solvent were added. Then lower the solution to thepresupposed temperature in a constant incubator. After stabilizing,H₂O₂(1.05 equiv, 35% w/w) was injected in one portion into the system.The mixture was stirred for 48 hours, and the termination of reactionwas monitored by TLC. The resulting suspension was quenched by saturatedNa₂S₂O₃. NaHCO₃ was used to wash, and then EtOAc (0.5 mL×3) was used forextraction, and the organic layers were combined and dried overanhydrous Na₂SO₄. The organic solvent was removed in rotary evaporator(the water-bathing temperature is under 38° C.), and the residues werepurified by chromatography on silica gel to afford the desired products.

(S)-2-(((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazoleor (S)-Lansoprazole (4)

81% yield; white solid; ¹H NMR (400 MHz, Acetone) δ 8.38 (d, J=5.6 Hz,1H), 7.75 (d, J=3.1 Hz, 2H), 7.40 (dd, J=6.1, 3.2 Hz, 2H), 7.13 (d,J=5.7 Hz, 1H), 4.93-4.90 (AB-system, J=13.5 Hz, 2H), 4.89-4.84 (q, J=7.8Hz, 2H), 2.33 (s, 3H); ¹³C NMR (101 MHz, Acetone) δ 162.69, 155.37,152.14, 149.15, 126.02, 124.16, 123.71, 123.27, 107.52, 66.50, 66.15,65.80, 65.44, 61.80, 61.75, 11.07; HRMS (ESI) calcd for C₁₆H₁₄F₃N₃O₂Sm/z [M+H]⁺: 370.0837; found: 370.0838; [α]_(D) ²²=−253.8 (c 0.5,Acetone); HPLC analysis: Chiralcel OD-H (Hex/IPA=80/20, 0.7 mL/min, 254nm, 22° C.), 22.9 (major), 33.3 min, 90% ee.

Example 5: Enantioselective Sulfoxidation of Phenyl Sulfides UsingTungstate System

To further demonstrate the substrate scope of this new method, severalconventional substrates containing phenyl sulfide moiety were alsotested (Scheme 3). For such substrates, a balance between reactionyields and enantioselectivities was achieved by employing a solventmixture between dimethyl carbonate (DMC) and ethers. The substrates(5a-5d) that could be tolerated included those with simple alkyl chainsto electron-withdrawing aromatic rings.

The following sulfoxide products were made from their reduced forms(5a-5d) via General Procedure 2, unless otherwise stated.

(S)-(butylsulfinyl)benzene (6a)

79% yield; colorless oil; ¹H NMR (400 MHz, CDCl₃) δ 7.63-7.58 (m, 2H),7.52-7.45 (m, 3H), 2.77 (dt, 2H), 1.79-1.65 (m, 1H), 1.64-1.51 (m, 1H),1.50-1.34 (m, 2H), 0.89 (t, J=7.3 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ143.97, 130.91, 129.18, 124.04, 57.01, 24.13, 21.87, 13.62; HRMS (ESI)calcd for C₁₀H₁₄OS m/z [M+H]⁺: 183.0844; found: 183.0849; [α]_(D)²²=−165.82 (c 0.73, CH₂Cl₂); HPLC analysis: Chiralcel OB-H(Hex/IPA=50/50, 0.5 mL/min, 254 nm, 22° C.), 9.5 (major), 12.2 min, 90%ee.

(S)-2-((phenylsulfinyl)methyl)naphthalene (6b)

93% yield; white solid; ¹H NMR (400 MHz, CDCl₃) δ 7.83-7.76 (m, 2H),7.71 (dd, J=8.6, 5.9 Hz, 2H), 7.50-7.42 (m, 4H), 7.39 (d, J=4.3 Hz, 4H),7.08 (dd, J=8.4, 1.7 Hz, 1H), 4.25 (d, J=12.6 Hz, 1H), 4.16 (d, J=12.6Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ 142.88, 133.18, 133.02, 131.30,129.93, 128.98, 128.23, 127.95, 127.81, 127.75, 126.71, 126.44, 126.41,124.56, 64.00; HRMS (ESI) calcd for C₁₇H₁₄OS m/z [M+H]⁺: 267.0844;found: 267.0850; [α]_(D) ¹²=−41.85 (c 1.3, CH₂Cl₂); HPLC analysis:Chiralcel OD-H (Hex/IPA=90/10, 1.0 mL/min, 254 nm, 22° C.), 18.7, 22.2(major) min, 86% ee.

(S)-1,2,3,4,5-pentafluoro-6-((phenylsulfinyl)methyl)benzene (6c)

82% yield; white solid; ¹H NMR (400 MHz, CDCl₃) δ 7.63-7.38 (m, 5H),4.19 (d, J=13.0 Hz, 1H), 4.09 (d, J=13.0 Hz, 1H); ¹³C NMR (101 MHz,CDCl₃) δ 142.57, 132.14, 129.45, 124.05, 50.40; HRMS (ESI) calcd forC₁₃H₇F₅OS m/z [M+H]⁺: 307.0216; found: 307.0221; [α]_(D) ²²=−102.15 (c1.5, CH₂Cl₂); HPLC analysis: Chiralcel OD-H (Hex/IPA=90/10, 1.0 mL/min,254 nm, 22° C.), 10.7, 12.1 (major) min, 90% ee.

(S)-1-((phenylsulfinyl)methyl)=4(trifluoromethyl)benzene (6d)

99% yield; white solid; ¹H NMR (400 MHz, CDCl₃) δ 7.56-7.30 (m, 7H),7.07 (d, J=8.0 Hz, 2H), 4.10 (d, J=12.7 Hz, 1H), 4.01 (d, J=12.7 Hz,1H); ¹³C NMR (101 MHz, CDCl₃) δ 142.36, 133.18, 131.55, 130.81, 129.15,125.37, 125.33, 124.39, 62.60; HRMS (ESI) calcd for C₁₄H₁₁F₃OS m/z[M+H]⁺: 285.0561; found: 285.0555; [α]_(D) ²²=−88.63 (c 1.5, CH₂Cl₂);HPLC analysis: Chiralcel OD-H (Hex/IPA=90/10, 1.0 mL/min, 254 nm, 22°C.), 12.7, 14.0 (major) min, 88% ee.

Example 6: Influence of Phosphate Loading

Synthetic Protocol: General Procedure 1

During optimization of the reaction conditions, it was found that theratio between Ag₂WO₄ to NaH₂PO₄ is crucial in obtaining good yields andenantioselectivities. As shown by Scheme 3, the most significantimprovement was achieved when the ratio of phosphate to tungstatereached 2:1.

As the amount of phosphate in this current methodology is in excess overtungstate, it was speculated that the Ishii-Venturello catalyst,[PO₄{WO(O₂)₂}₄]³⁻, is not the active catalyst in this methodology. WhenAg₂WO₄/NaH₂PO₄ was replaced with H₃PW₁₂O₄₀ (Keggin's reagent) as inIshii's protocol, the reaction provided sulfoxides in 40% yield and 30%ee. The search for the active species is further explored in Example 7.

Example 7: Characterization of Tungstate Anion

Ligand coordination or substitution has been previously shown to be animportant factor that can influence the catalytic activities ofperoxotungstates. Under the current experimental condition, monomericand oligomeric dihydroxide species i (see FIG. 11) should exist and inthe presence of phosphate additive, form substituted phosphate speciesii-iv [S. Campestrini, et al., J. Org. Chem. 1988, 53, 5721; C. H. Yang,et al., J. Chem. Soc., Chem. Commun. 1985, 20, 1425; G. Amato, et al.,J. Mol. Catal. 1986, 37, 165]. These complexes assume distortedpentagonal bipyramid geometry and obey the 18-electron rule. As aresult, coordination of three or more phosphates to the tungstate centercan be considered to be unlikely. It is also important to note that dueto the short O—O bond distances (1.45 to 1.47 Å) (S. E. Jacobson, R.Tang, F. Mares, Inorg. Chem. 1978, 17, 3055) in the peroxo group, theoxygen atoms will most likely lie in the equatorial plane, instead ofoccupying both axial and equatorial positions in the complex. Based onthese premises, the four possible configurations of substitutedperoxotungstate species are presented (FIG. 11).

Preparation of Active Species

To identify the active species in the tungstate-catalyzed Sulfoxidation,in a 4 mL sample vial, BG-1 (0.01 mmol, 1.0 equiv), tungstate oxide(0.01 mmol, 1.0 equiv), phosphate monobasic (0.05 mmol, 5.0 equiv),hydrogen peroxide (0.1 mmol, 10.0 equiv, 35% w/w) and diethyl ether in aproper amount were added at room temperature and stirred for 6 hours,and filtrate the precipitate. The mixture was blown dry, and thenremoved of water in vacuo. FIG. 1A shows the Raman spectrum of theactive species. Raman setting: 2 mW, 532 laser power, 30 seconds.

Comparison of Experimental and Computated Raman Spectra

The experimental Raman spectra of the active species was compared withpredicted Raman spectra of the four possible intermediates (see FIG.11). Computed Raman spectra were obtained by performing vibrationalfrequency analysis on stationary points optimized at the B3LYP/B1 levelof theory in gas phase, where B1 is a combination of LANL2DZ effectivecore potential basis set for W and the 6-31g* basis set for remainingatoms.

The peak at 1014 cm⁻¹ in experimental Raman spectra (see FIG. 1A) wasfound to be the peak with the highest intensity, which corresponds tothe W═O bond stretching vibrations. Computed Raman spectra showed thispeak at 920-1000 cm⁻¹ region. Additionally, characteristic bands fromW(O₂) group appear in 500-600 cm⁻¹ region, while bands above 1000 cm⁻¹generally correspond to vibrational modes from phosphate group.

A peak was observed experimentally at 711 cm⁻¹, which corresponds to thetwisting of P—O—H group in the phosphate ligand (FIG. 1A). This samepeak was found only in the computed spectra of P2W (713 cm⁻¹) (see FIG.11D). A more thorough analysis of the P2W structures revealed thatintramolecular hydrogen bond interaction between the two phosphateligands is important for this peak; absence of such interaction willshift the vibrational frequency towards 800 cm⁻¹. It is thus proposedthat the active anion of this enantioselective sulfoxidation isdiphosphatobisperoxotungstate, [{PO₂(OH)₂}₂{WO(O₂)₂}]²⁻.

Example 8: Computational Studies of Ion-Pair BG1-P2W

Preliminary computational studies of the complete ion-pair BG1-P2Wstructure using ONIOM method revealed a stable ion-pair interaction,where P2W is buried in the chiral cavity of BG1 (FIG. 2). Thisconfiguration results in only one of the peroxo-oxygen (marked as Oc inFIG. 2) being exposed, leaving it as the only possible reaction site.Without wishing to be bound by theory, it is hypothesized that thisconfiguration will restrict the direction of approach of the sulfide,thereby providing fertile condition for an enantioselective reaction. Asimple working model, which includes the initial formation of P2W in theaqueous phase through the interactions of silver tungstate, phosphateand hydrogen peroxide is thus proposed (FIG. 3). The formation of theion-pair BG1-P2W in the organic phase is facilitated by BG1. Afteroxidation, P2W is regenerated in the aqueous phase by H₂O₂.

Example 9: Optimization of Reaction Conditions for Molybdate-CatalyzedOxidation

TABLE 2 Asymmetric oxidation of methyl ester of methyl diphenyl methylmercapto acetate (MDMMA) to methyl diphenyl methyl sulfinyl acetate(MDMSA) by using aqueous H₂O₂.

Entry [Mo] Additive Solvent time yield (%)^(b) ee (%)^(c)   1^(d)(NH₄)₆Mo₇O₂₄•4H₂O — Toluene 24  0  0  2 (NH₄)₆Mo₇O₂₄•4H₂O — Toluene 2415  0   3^(d) (NH₄)₆Mo₇O₂₄•4H₂O CH₃CO₂H (1.0 equiv.) Toluene 24  0  0  4(NH₄)₆Mo₇O₂₄•4H₂O CH₃CO₂H (1.0 equiv.) Toluene 24 14 20  5(NH₄)₆Mo₇O₂₄•4H₂O CF₃CO₂H (1.0 equiv.) Toluene  8 80  4  6(NH₄)₆Mo₇O₂₄•4H₂O NaHSO₄ (1.0 equiv.) Toluene 19 99 69  7(NH₄)₆Mo₇O₂₄•4H₂O KHSO₄ (1.0 equiv.) Toluene 19 99 75  8(NH₄)₆Mo₇O₂₄•4H₂O LiH₂PO₄ (1.0 equiv.) Toluene 19 50 40  9(NH₄)₆Mo₇O₂₄•4H₂O Na₂HPO₄ (1.0 equiv.) Toluene 19 28  0 10 Li₂MoO₄ KHSO₄(1.0 equiv.) Toluene  3 85 88 11 Na₂MoO₄•2H₂O KHSO₄ (1.0 equiv.) Toluene 2 99 88 12 K₂MoO₄ KHSO₄ (1.0 equiv.) Toluene  2 99 86 13 Na₂MoO₄•2H₂OKHSO₄ (0.5 equiv.) Toluene  2 99 89 14 Na₂MoO₄•2H₂O KHSO₄ (0.25 equiv.)Toluene  2 99 83 15 Na₂MoO₄•2H₂O KHSO₄ (0.5 equiv.) Xylene   2.5 99 9216 Na₂MoO₄•2H₂O KHSO₄ (0.5 equiv.) ^(i)Pr₂O  1 99 93  17^(e)Na₂MoO₄•2H₂O KHSO₄ (0.5 equiv.) ^(i)Pr₂O  1 99 94 Unless otherwiseindicated, reaction was performed with 0.05 mmol of 7a in the presenceof 1 mol % of chiral bisguanidinium (S,S)-1a and 5 mol % of molybdatessalts [Mo] in 1.0 mL of solvent. ^(b)Yield of the isolated product.^(c)Determined by HPLC analysis using Chiralcel AD-H column. dWithout(S,S)-1a. ^(e)Reaction was conducted using 0.2 mmol of 7a at 0° C. with2.5 mol % Na₂MoO₄•2H₂O.

As set out in Table 2, reaction conditions for molybdate-catalyzedsulfoxidation were optimized by varying, for example, the identity andamount of molybdate-containing salt, the sulfate-containing additive andthe solvent. General Procedure 3 was applied as the synthetic protocol.

During our continuous efforts on the synthesis of enantioenrichedsulfoxide compounds, it was observed that general electrophilica-halogenated carboxylates are incompatible with the reaction conditionsfor the in situ generated sulfenate anion through retro-Michael process,even though benzyl bromide and alkyl iodide derivatives are suitable(see FIG. 15). Meanwhile, considering the high oxidative efficiency ofthe anionic peroxomolybdate species, a direct oxidation of 2-thioacetate to afford 2-sulfinyl acetate was conducted by utilizingmolybdate salts in catalytic amount and stoichiometric aqueous H₂O₂co-oxidant.

Methyl ester of methyl diphenyl methyl mercapto acetate (MDMMA) 7a waschosen as the model substrate (Table 2) for investigation since theoxidative product methyl diphenyl methyl sulfinyl acetate (MDMSA) 8a canbe easily transformed to modafinil [James Ternois, et al., Tetrahedron:Asymmetry 18, 2959-2964 (2008); Ganapati D. Yadav, et al., Org. ProcessRes. Dev. 14, 537-543 (2010); Zheng-Zheng Li, et al., Eur. J. Inorg.Chem. 2015, 4335-4342 (2015)], which cannot be achieved by using theretro-Michael sulfenate anion strategy (see FIG. 15).

The reaction was initially performed in the absence of bisguanidiniumphase transfer catalyst (Table 2, entry 1) by using 5 mol % of(NH₄)₆Mo₇O₂₄.4H₂O with 35% aqueous H₂O₂ as the terminal co-oxidant intoluene at room temperature. As expected, no oxidative product wasobtained after 24 h and the starting material 7a was fully recovered.However, the addition of 1 mol % of bisguanidinium (S,S)-1a can slightlypromote the proceedings of the oxidation, despite the low yield (15%,Table 2, entry 2) and no enantioselectivity. Acetic acid is frequentlyused as an additive in oxidation reactions for tuning the reactivity andselectivity (Liang Hong, et al., Chem. Rev. (2016)). Nevertheless, theoutcome was still disappointing in low reactivity (Table 2, entries 3and 4), even though a slightly higher enantioselectivity of 20% can beobtained. The addition of trifluoroacetic acid provided a dramaticenhancement of reactivity was achieved but with a negligibleenantioselectivity (Table 2, entry 5). The addition of one equivalent ofhydrogen sulfate (H. Firouzabadi, et al., Adv. Synth. Catal. 348,434-438 (2006)) salts surprisingly resulted in a significant improvementof yield as well as enantioselectivity (Table 2, entries 6 and 7).Switching to other additives such as dihydrogen phosphate or hydrogenphosphate led to poor results (Table 2, entries 8 and 9). Upon furtheroptimizations (Table 2, entries 9-16), it was found that the use of 5mol % of Na₂MoO₄.2H₂O with 0.5 equivalent of KHSO₄ and 1 mol % of(S,S)-1a resulted in a superior system for the oxidation of MDMMA 7a in^(i)Pr₂O with aqueous H₂O₂ as co-oxidant (Table 2, entry 16). Finally,the optimal conditions were further established by lowering thetemperature to 0° C. to afford the desired product 8a in 99% yield with94% ee. The absolute configuration of 8a was confirmed to be S bycomparison with the data in reported literatures (Thomas Prisinzano, et.al., Tetrahedron: Asymmetry 15, 1053-1058 (2004)).

(S)-methyl 2-(benzhydrylsulfinyl)acetate (8a) was made from 7a, viaGeneral Procedure 3

White solid; 99% yield; mp: 103.8-105.5° C.; ¹H NMR (400 MHz, CDCl₃) δ7.50 (dd, J=11.6, 7.9 Hz, 4H), 7.44-7.28 (m, 6H), 5.21 (s, 1H), 3.74 (s,3H), 3.48 (dd, J=45.5, 14.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 165.78,135.21, 133.77, 129.55, 129.27, 128.78, 128.75, 128.56, 128.51, 71.55,54.02, 52.74; IR: 1732.08, 1492.90, 1361.74, 1234.44, 1176.58, 1045.42,975.98, 702.09 cm⁻¹; HRMS (ESI) calcd for C₁₆H₁₆O₃S m/z [M+H]⁺:289.0898; found: 289.0892; HPLC analysis: Chiralcel AD-H (Hex/IPA=50/50,1.0 mL/min, 230 nm, 22° C.), 7.0 (major), 12.6 min, 94% ee; [α]_(D)²²=+19.24 (c 5.51, MeOH).

Example 10: Asymmetric Sulfoxidation of Aliphatic 2-Thio Acetate byChiral Bisguanidinium (S,S)-1a

TABLE 3 Asymmetric Sulfoxidation of Aliphatic 2-thio Acetate By ChiralBisguanidinium (S,S)-1a.

time yield ee entry R 3 (h) (%)^(b) (%)^(c) 1 Ph 8b   0.8 99 90 24-MeC₆H₄ 8c 1 92 92  3^(d) 4-MeOC₆H₄ 8d 1 96 83 4 4-FC₆H₄ 8e 1 94 96 54ClC₆H₄ 8f 1 92 91 6 2-MeC₆H₄ 8g 1 98 92 7 2-ClC₆H₄ 8h 1 98 93 82-BrC₆H₄ 8i 1 99 93  9^(d) 2-thienyl 8j 1 94 89 10^(d)

8k 1 83 37 Unless otherwise stated, reaction was performed with 0.2 mmolof 7 in the presence of 1 mol % of chiral bisguanidinium (S,S)-1a and2.5 mol % of Na₂MoO₄.2H₂O in 1.0 mL of ^(i)Pr₂O at 0° C. ^(b)Yield ofthe isolated product. ^(c)Determined by HPLC analysis. ^(d)1.0 mL of^(n)Bu₂O was used as solvent.

The optimized reaction conditions as provided by the previous example(see entry 17, Table 2) was applied to general aliphatic 2-thio acetatesubstrates. ^(n)Bu₂O solvent was used in certain cases to improve theenantioselectivities. It was found that the oxidation of substrates 7proceeded rapidly to furnish sulfoxide products 8b-8k within 1 h.Generally, simple benzyl 2-thio acetates with different substitutionpatterns on the aromatic ring were well tolerated (Table 3, entries1-8). Both electron-rich and electron-deficient substituents present inpara- or ortho-position of the phenyl moiety resulted in excellentoutcome. In most cases, high enantioselectivities (>90% ee) wereobserved, though a slight decrease in enantioselectivity was achievedfor 4-methoxy substituted substrate (Table 2, entry 3, 83% ee).Substrate with heterocyclic moiety such as oxidant-sensitive 2-thienylgroup was also investigated, providing the desired sulfoxide 8j inexcellent yield with good enantioselectivity (Table 3, entry 9).However, tert-butyl substituted 2-thio acetate was a less favourablesubstrate, leading to low enantioselectivity (Table 3, entry 10). Theabsolute configuration of product 8f was confirmed to be R usingsingle-crystal X-ray diffraction; thus, the absolute configuration ofsulfoxides 8 was assigned by analogy to 8f.

The following sulfoxide products are made from their reduced forms(7b-7k) via General Procedure 3, unless otherwise stated.

(R)-tert-butyl 2-(benzylsulfinyl)acetate (8b), from 7b

White solid; 90% yield; mp: 83.8-85.1° C.; ¹H NMR (400 MHz, CDCl₃) δ7.38 (t, J=6.7 Hz, 3H), 7.35-7.29 (m, 2H), 4.16 (dd, J=62.7, 13.0 Hz,2H), 3.46 (q, J=14.0 Hz, 2H), 1.50 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ164.33, 130.37, 129.12, 128.98, 128.59, 83.50, 57.69, 54.68, 28.03; IR:1735.93, 1454.33, 1396.46, 1276.88, 1257.59, 1161.15, 1029.99, 952.84,767.67, 702.09, 416.62 cm⁻¹; HRMS (ESI) calcd for C₁₃H₁₈O₃S m/z [M+H]⁺:255.1055; found: 255.1054; HPLC analysis: Chiralcel AD-H (Hex/IPA=90/10,1.0 mL/min, 230 nm, 22° C.), 9.8 (major), 16.4 min, 90% ee; [α]_(D)²²=+18.77 (c 5.03, MeOH).

(R)-tert-butyl 2-((4-methylbenzyl)sulfinyl)acetate (8c), from 7c

White solid; 92% yield; mp: 99.8-102.0° C.; ¹H NMR (400 MHz, CDCl₃) δ7.23-7.16 (m, 4H), 4.11 (dd, J=59.9, 13.0 Hz, 2H), 3.44 (q, J=14.0 Hz,2H), 2.35 (s, 3H), 1.49 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 164.37,138.47, 130.22, 129.66, 125.91, 83.38, 57.40, 54.61, 28.00, 21.15; IR:1728.22, 1516.05, 1300.02, 1149.57, 1118.71, 1022.27, 956.69, 821.68,736.81, 466.77 cm⁻¹; HRMS (ESI) calcd for C₁₄H₂₀O₃S m/z [M+H]⁺:269.1211; found: 269.1211; HPLC analysis: Chiralcel AD-H (Hex/IPA=90/10,1.0 mL/min, 230 nm, 22° C.), 9.8 (major), 15.1 min, 92% ee; [α]_(D)²²=+14.83 (c 4.86, MeOH).

(R)-tert-butyl 2-((4-methoxybenzyl)sulfinyl)acetate (8d) from 7d

White solid; 96% yield; mp: 92.1-93.3° C.; ¹H NMR (400 MHz, CDCl₃) δ7.27 (d, J=8.4 Hz, 2H), 6.91 (t, J=10.6 Hz, 2H), 4.12 (dd, J=64.6, 13.2Hz, 2H), 3.82 (s, 3H), 3.45 (q, J=14.0 Hz, 2H), 1.51 (s, 9H); ¹³C NMR(100 MHz, CDCl₃) δ 164.38, 159.87, 131.56, 120.84, 114.40, 83.39, 56.91,55.27, 54.44, 28.01; IR: 1728.22, 1612.49, 1516.05, 1465.90, 1392.61,1369.46, 1303.88, 1253.73, 1176.58, 1149.57, 1118.71, 1033.85, 837.11,732.95 cm⁻¹; HRMS (ESI) calcd for C₁₄H₂₀O₄S m/z [M+H]⁺: 285.1261; found:285.1262; HPLC analysis: Chiralcel AD-H (Hex/IPA=90/10, 1.0 mL/min, 230nm, 22° C.), 13.9 (major), 21.3 min, 83% ee; [α]_(D) ²²=+16.13 (c 5.43,MeOH).

(R)-tert-butyl 2-((4-fluorobenzyl)sulfinyl)acetate (8e) from 7e

White solid; 94% yield; mp: 95.5-96.2° C.; ¹H NMR (400 MHz, CDCl₃) δ7.35-7.27 (m, 2H), 7.07 (t, J=8.6 Hz, 2H), 4.11 (dd, J=76.1, 13.2 Hz,2H), 3.53-3.35 (m, 2H), 1.49 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) 164.21,162.92 (d, J=248.0 Hz), 132.11 (d, J=8.3 Hz), 124.92 (d, J=3.0 Hz),115.94 (d, J=21.7 Hz), 83.56, 56.54, 54.60, 27.99; ¹⁹F NMR (376 MHz,CDCl₃) δ −112.91; IR: 1716.65. 1508.33, 1369.46, 1300.02, 1226.73,1145.72, 1114.86, 1029.99, 840.96, 740.67, 528.50 cm⁻¹; HRMS (ESI) calcdfor C₁₃H₁₇FO₃S m/z [M+H]⁺: 273.0961; found: 273.0952; HPLC analysis:Chiralcel AD-H (Hex/IPA=90/10, 1.0 mL/min, 230 nm, 22° C.), 11.2(major), 17.5 min, 96% ee; [α]_(D) ²²=+29.96 (c 4.91, MeOH).

(R)-tert-butyl 2-((4-chlorobenzyl)sulfinyl)acetate (8f) from 7f

White solid; 92% yield; mp: 84.1-85.3° C.; ¹H NMR (400 MHz, CDCl₃) δ7.36 (d, J=8.4 Hz, 2H), 7.26 (d, J=8.4 Hz, 2H), 4.10 (dd, J=76.9, 13.2Hz, 2H), 3.50-3.36 (m, 1H), 1.49 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ164.16, 134.74, 131.68, 129.11, 127.59, 83.60, 56.63, 54.65, 27.98; IR:1724.36, 1712.79, 1597.06, 1492.90, 1454.33, 1369.46, 1303.88, 1261.45,1145.72, 1095.57, 1018.41, 956.69, 914.26, 840.96, 740.67, 702.09,671.23 cm⁻¹; HRMS (ESI) calcd for C₁₃H₁₇ClO₃S m/z [M+H]⁺: 289.0665;found: 289.0668; HPLC analysis: Chiralcel AD-H (Hex/IPA=90/10, 1.0mL/min, 230 nm, 22° C.), 11.9 (major), 18.5 min, 91% ee; [α]_(D)²²=+43.89 (c 5.21, MeOH).

A single crystal structure of (R)-8f is provided in FIG. 10A. Crystaldata for (R)-8f: [C₁₃H₁₇ClO₃S], M=288.77, orthorhombic, P 21 21 21,a=5.2790(5), b=11.5315(8), c=23.4325(19) Å, α=90, β=90°, γ=90°,V=1426.4(2) Å³, Z=4, ρ_(calcd)=1.345 g/cm³, μ(CuKα)=0.412 mm⁻¹, T=103(2)K, Wavelength=0.71073 Å, colorless block. Bruker X8 CCD X-raydiffractionmeter; 3281 independent measured reflections, F² refinement,R₁(obs)=0.0377, wR₂(all)=0.0808, 3001 independent observedabsorption-corrected reflections, 242 parameters. Crystallographic datafor this paper have been deposited at the Cambridge CrystallographicData Centre under deposition number CCDC 1456988.

(R)-tert-butyl 2-((2-methylbenzyl)sulfinyl)acetate (8g) from 7g

Colourless oil; 98% yield; ¹H NMR (400 MHz, CDCl₃) δ 7.34-7.09 (m, 4H),4.20 (dd, J=65.0, 12.9 Hz, 2H), 3.55 (dd, J=31.3, 13.9 Hz, 2H), 2.39 (s,3H), 1.47 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 164.37, 137.70, 131.29,130.86, 128.77, 128.31, 126.54, 83.48, 56.89, 55.84, 28.01, 19.82; IR:1732.08, 1712.79, 1492.90, 1454.33, 1392.61, 1369.46, 1288.45, 1261.45,1161.15, 1041.56, 952.84, 910.40, 837.11, 767.67, 482.20 cm⁻¹; HRMS(ESI) calcd for C₁₄H₂₀O₃S m/z [M+H]⁺: 269.1211; found: 269.1210; HPLCanalysis: Chiralcel AD-H (Hex/IPA=90/10, 1.0 mL/min, 230 nm, 22° C.),8.2 (major), 15.6 min, 92% ee; [α]_(D) ²²=+55.71 (c 5.15, MeOH).

(R)-tert-butyl 2-((2-chlorobenzyl)sulfinyl)acetate (8h) from 7h

Colourless oil; 98% yield; ¹H NMR (400 MHz, CDCl₃) δ 7.47-7.40 (m, 2H),7.35-7.27 (m, 2H), 4.32 (dd, J=96.1, 12.9 Hz, 2H), 3.58 (dd, J=43.2,13.9 Hz, 2H), 1.50 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 164.19, 134.66,132.77, 130.04, 129.90, 127.99, 127.32, 83.57, 56.18, 55.96, 28.00; IR:1728.22, 1712.79, 1473.62, 1446.61, 1392.61, 1369.46, 1296.16, 1261.45,1157.29, 1053.13, 952.84, 910.40, 840.96, 763.81, 682.80, 578.64 cm⁻¹;HRMS (ESI) calcd for C₁₃H₁₇ClO₃S m/z [M+H]⁺: 289.0665; found: 289.0665;HPLC analysis: Chiralcel AD-H (Hex/IPA=90/10, 1.0 mL/min, 230 nm, 22°C.), 10.4 (major), 32.7 min, 93% ee; [α]_(D) ²²=+47.96 (c 5.55, MeOH).

(R)-tert-butyl 2-((2-bromobenzyl)sulfinyl)acetate (8i) from 7i

Pale yellow oil; 99% yield; ¹H NMR (400 MHz, CDCl₃) δ 7.61 (dd, J=8.0,1.1 Hz, 1H), 7.43 (dd, J=7.6, 1.7 Hz, 1H), 7.32 (td, J=7.5, 1.2 Hz, 1H),7.21 (td, J=7.7, 1.7 Hz, 1H), 4.33 (dd, J=99.7, 12.9 Hz, 2H), 3.59 (dd,J=46.8, 13.8 Hz, 2H), 1.50 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 164.15,133.22, 132.78, 130.21, 129.83, 127.93, 125.10, 83.56, 58.53, 56.20,28.00; IR: 1728.22, 1712.79, 1566.20, 1469.76, 1392.61, 1369.46,1296.16, 1261.45, 1157.29, 1045.42, 1029.99, 952.84, 910.40, 837.11,763.81, 659.66 cm⁻¹; HRMS (ESI) calcd for C₁₃H₁₇BrO₃S m/z [M+H]⁺:333.0160; found: 333.0170; HPLC analysis: Chiralcel AD-H (Hex/IPA=90/10,1.0 mL/min, 230 nm, 22° C.), 10.7 (major), 40.1 min, 93% ee; [α]_(D)²²=+45.04 (c 6.6, MeOH).

(S)-tert-butyl 2-((thiophen-2-ylmethyl)sulfinyl)acetate (8j) from 7j

White solid; 94% yield; mp: 67.7-68.4° C.; ¹H NMR (400 MHz, CDCl₃) δ7.33 (dd, J=5.1, 1.2 Hz, 1H), 7.09 (d, J=2.8 Hz, 1H), 7.06 (dd, J=5.0,3.5 Hz, 1H), 4.37 (dd, J=62.5, 14.1 Hz, 2H), 3.47 (q, J=14.2 Hz, 2H),1.50 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 164.19, 129.36, 129.28, 127.59,127.10, 83.59, 54.30, 51.72, 28.03; IR: 1728.22, 1712.79, 1454.33,1392.61, 1369.46, 1288.45, 1257.59, 1161.15, 1041.56, 952.84, 906.54,840.96, 582.50, 474.49 cm⁻¹; HRMS (ESI) calcd for C₁₁H₁₆O₃S₂ m/z [M+H]⁺:261.0619; found: 261.0611; HPLC analysis: Chiralcel AD-H (Hex/IPA=90/10,1.0 mL/min, 230 nm, 22° C.), 10.4 (major), 17.3 min, 89% ee; [α]_(D)²²=+18.2 (c 4.80, MeOH).

(S)-tert-butyl 2-(tert-butylsulfinyl)acetate (8k) from 7k

White solid; 83% yield; mp: 95.7-96.8° C.; ¹H NMR (400 MHz, CDCl₃) δ3.37 (dd, J=60.6, 13.6 Hz, 2H), 1.49 (s, 9H), 1.27 (s, 9H); ¹³C NMR (100MHz, CDCl₃) δ 165.35, 83.20, 54.08, 52.83, 27.96, 22.71; IR: 1728.22,1716.65, 1462.04, 1392.61, 1365.60, 1288.45, 1261.45, 1165.00, 1141.86,1041.56, 956.69, 894.97, 840.96, 736.81 cm⁻¹; HRMS (ESI) calcd forC₁₀H₂₀O₃S m/z [M+H]⁺: 221.1211; found: 221.1209; HPLC analysis:Chiralcel OD-H (Hex/IPA=95/5, 1.0 mL/min, 230 nm, 22° C.), 10.0 (major),11.5 min, 37% ee; [α]_(D) ²²=−33.03 (c 3.6, MeOH).

Example 11: Asymmetric Sulfoxidation of Aromatic 2-Thio Acetate

TABLE 4 Asymmetric Sulfoxidation of Aromatic 2-thio acetate by Chiralbisguanidinium (S,S)-1a.

Entry Ar 10 time (h) yield (%)^(b) ee (%)^(c)  1 Ph 10a 1 91 86  24-MeC₆H₄ 10b 1 93 83  3 4-MeOC₆H₄ 10c 1 94 79   4^(d) 4-FC₆H₄ 10d 1 9389  5 4-ClC₆H₄ 10e 1 93 90  6 4-BrC₆H₄ 10f 1 95 91  7 2-MeC₆H₄ 10g 1 9982   8^(d) 2-MeOC₆H₄ 10h 1 99 89  9 2-ClC₆H₄ 10i 4 99 81 101-naphthalenyl 10j 1 97 83  11^(e) 2-pyridyl 10k 4 99 52  12^(f)2-benzothiazoly1 10l 24  79 74 Unless otherwise stated, reaction wasperformed with 0.2 mmol of 9 in the presence of 1 mol % of chiralbisguanidinium (S,S)-1a and 2.5 mol % of K₂MoO₄ in 1.0 mL of ^(i)Pr₂O at0° C. ^(b)Yield of the isolated product. ^(c)Determined by HPLCanalysis. ^(d)1.0 mL of ^(n)Bu₂O was used as solvent. ^(e)At roomtemperature. ^(f)The reaction was conducted at room temperature using1.5 equiv. of 35% aqueous H₂O₂.

Aromatic 2-thio acetate substrates 9a-9l were prepared and examined inaccordance with the procedure set out under Synthesis of Aromatic 2-thioacetate. Based on General Procedure 3 and some modifications, efficientoxidation of 9a-91 with a variety of substitution patterns was achievedby using 0.25 equivalent of KHSO₄ in the presence of 2.5 mol % of K₂MoO₄(Table 4). Good to excellent yields and enantioselectivities wereachieved in most cases. Generally, the reaction can be completed in lessthan one hour. However, for specific substrates with steric hindrance(Table 4, entry 10) or 2-pyridyl, 2-benzothiazolyl moieties (Table 4,entries 11 and 12), longer reaction time was required to achieveacceptable yield. Moreover, for less reactive substrates 9k and 9l, thereaction was conducted at elevated temperature (room temperature) withmoderate enantioselectivities. Nevertheless, 2-benzothiazolylsubstituted substrate 9l cannot be completely consumed within 24 h evenwith the addition 1.5 equivalent of aqueous hydrogen peroxide oxidant(Table 4, entry 12). The absolute configuration of product 10f wasconfirmed to be S using single-crystal X-ray diffraction; thus, theabsolute configuration of sulfoxides 10 was assigned by analogy to 10f.

Characterization of Sulfoxide Products

(S)-tert-butyl 2-(phenylsulfinyl)acetate (10a), from 9a

Yellow oil; 91% yield; ¹H NMR (400 MHz, CDCl₃) δ 7.70 (dd, J=6.7, 3.0Hz, 2H), 7.54 (dd, J=6.5, 2.7 Hz, 3H), 3.70 (dd, J=80.0, 13.7 Hz, 2H),1.39 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 163.77, 143.29, 131.65, 129.30,124.42, 83.25, 62.61, 27.88; IR: 1728.22. 1712.79, 1477.47, 1446.61,1392.61, 1369.46, 1296.16, 1261.45, 1157.29, 1126.43, 1049.28, 952.84,902.69, 840.96, 690.52, 667.37 cm⁻¹; HRMS (ESI) calcd for C₁₂H₁₆O₃S m/z[M+H]⁺: 241.0898; found: 241.0900; HPLC analysis: Chiralcel OD-H(Hex/IPA=90/10, 1.0 mL/min, 254 nm, 22° C.), 8.9, 11.6 (major) min, 86%ee; [α]_(D) ²²=−122.64 (c 4.31, MeOH).

(S)-tert-butyl 2-(p-tolylsulfinyl)acetate (10b), from 9b

Pale yellow oil; 93% yield; ¹H NMR (400 MHz, CDCl₃) δ 7.58 (d, J=8.1 Hz,2H), 7.33 (d, J=7.9 Hz, 2H), 3.68 (dd, J=89.1, 13.6 Hz, 2H), 2.42 (s,3H), 1.40 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 163.85, 142.26, 140.03,129.97, 124.48, 83.16, 62.68, 27.88, 21.44; IR: 1724.36, 1492.90,1454.33, 1392.61, 1369.46, 1292.31, 1261.45, 1161.15, 1126.43, 1083.99,1049.28, 840.96, 813.96 cm⁻¹; HRMS (ESI) calcd for C₁₃H₁₈O₃S m/z [M+H]⁺:255.1055; found: 255.1056; HPLC analysis: Chiralcel OB-H (Hex/IPA=90/10,1.0 mL/min, 230 nm, 22° C.), 7.3 (major), 8.8 min, 83% ee; [α]_(D)²²=−114.17 (c 4.58, MeOH).

(S)-tert-butyl 2-((4-methoxyphenyl)sulfinyl)acetate (10c), from 9c

Pale yellow oil; 94% yield; ¹H NMR (400 MHz, CDCl₃) δ 7.64 (d, J=8.7 Hz,2H), 7.03 (d, J=8.7 Hz, 2H), 3.86 (s, 3H), 3.70 (dd, J=108, 13.6 Hz,2H), 1.39 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 163.84, 162.47, 134.10,126.53, 114.78, 83.11, 62.68, 55.55, 27.89; IR: 1728.22, 1712.79,1593.20, 1496.76, 1462.04, 1392.61, 1369.46, 1296.16, 1257.59, 1161.15,1122.57, 1087.85, 1029.99, 952.84, 902.69, 833.25, 798.53, 756.10,667.37 cm⁻¹; HRMS (ESI) calcd for C₁₃H₁₈O₄S m/z [M+H]⁺: 271.1004; found:271.1007; HPLC analysis: Chiralcel OB-H (Hex/IPA=90/10, 1.0 mL/min, 230nm, 22° C.), 11.8 (major), 14.9 min, 79% ee; [α]_(D) ²²=−91.45 (c 4.97,MeOH).

(S)-tert-butyl 2-((4-fluorophenyl)sulfinyl)acetate (10d), from 9d

White solid; 93% yield; mp: 95.1-95.8° C.; ¹H NMR (400 MHz, CDCl₃) δ7.70 (ddd, J=8.4, 5.1, 1.3 Hz, 2H), 7.25-7.17 (m, 2H), 3.69 (ddd,J=87.8, 13.7, 1.0 Hz, 2H), 1.39 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ165.92, 163.50 (d, J=18.4 Hz), 138.73 (d, J=3.0 Hz), 126.86 (d, J=9.0Hz), 116.63 (d, J=22.6 Hz), 83.38, 62.63, 27.86; ¹⁹F NMR (376 MHz,CDCl₃) δ −107.41; IR: 1724.36, 1585.49, 1492.90, 1469.76, 1369.46,1296.16, 1257.59, 1215.15, 1157.29, 1080.14, 1037.70, 837.11 cm⁻¹; HRMS(ESI) calcd for Cl₂H₁₅FO₃S m/z [M+H]⁺: 259.0804; found: 259.0804; HPLCanalysis: Chiralcel OD-H (Hex/IPA=90/10, 1.0 mL/min, 230 nm, 22° C.),8.7, 9.7 (major) min, 89% ee; [α]_(D) ²²=−115.46 (c 4.74, MeOH).

(S)-tert-butyl 2-((4-chlorophenyl)sulfinyl)acetate (10e), from 9e

Pale yellow solid; 93% yield; mp: 115.4-116.9° C.; ¹H NMR (400 MHz,CDCl₃) δ 7.65 (d, J=8.5 Hz, 2H), 7.52 (d, J=8.5 Hz, 2H), 3.69 (dd,J=77.7, 13.8 Hz, 2H), 1.41 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 163.58,141.86, 137.94, 129.61, 125.88, 83.54, 62.58, 27.92; IR: 1724.36,1573.91, 1477.47, 1369.46, 1157.29, 1087.85, 1037.70, 1010.70, 825.53,740.67 cm⁻¹; HRMS (ESI) calcd for C₁₂H₁₅ClO₃S m/z [M+H]⁺: 275.0509;found: 275.0507; HPLC analysis: Chiralcel OB-H (Hex/IPA=90/10, 1.0mL/min, 230 nm, 22° C.), 8.1 (major), 9.4 min, 90% ee; [α]_(D)²²=−136.61 (c 4.96, MeOH).

(S)-tert-butyl 2-((4-bromophenyl)sulfinyl)acetate (10f), from 9f

Pale yellow solid; 95% yield; mp: 99.2-100.4° C.; ¹H NMR (400 MHz,CDCl₃) δ 7.68 (d, J=8.6 Hz, 2H), 7.58 (d, J=8.6 Hz, 2H), 3.69 (dd,J=75.2, 13.8 Hz, 2H), 1.42 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 163.57,142.47, 132.54, 126.19, 126.02, 83.56, 62.51, 27.92; IR: 1724.36,1570.06, 1469.76, 1369.46, 1300.02, 1257.59, 1149.57, 1045.42, 1006.84,821.68, 721.38 cm⁻¹; HRMS (ESI) calcd for Cl₂H₁₅BrO₃S m/z [M+H]⁺:319.0004; found: 319.0013; HPLC analysis: Chiralcel OB-H (Hex/IPA=90/10,1.0 mL/min, 230 nm, 22° C.), 9.0 (major), 10.4 min, 91% ee; [α]_(D)²²=−123.13 (c 4.95, MeOH).

A single-crystal structure of (S)-10f is provided in FIG. 10B. Crystaldata for (S)-10f: [C₁₂H₁₅BrO₃S], M=319.21, monoclinic, P 1 21 1,a=26.8296(16), b=9.6925(5), c=10.5106(6) Å, α=90, β=101.2326(19)°,γ=90°, V=2680.9(3) Å³, Z=8, ρ_(calcd)=1.582 g/cm³, μ(CuKα)=3.216 mm⁻¹,T=103(2) K, Wavelength=0.71073 Å, colorless plate. Bruker X8 CCD X-raydiffractionmeter; 22922 independent measured reflections, F² refinement,R₁(obs)=0.0620, wR₂(all)=0.1213, 10957 independent observedabsorption-corrected reflections, 626 parameters. Crystallographic datafor this paper have been deposited at the Cambridge CrystallographicData Centre under deposition number CCDC 1456989.

(S)-tert-butyl 2-(o-tolylsulfinyl)acetate (10g), from 9g

Pale yellow oil; 99% yield; ¹H NMR (400 MHz, CDCl₃) δ 7.93 (dd, J=7.5,1.7 Hz, 1H), 7.49-7.35 (m, 2H), 7.20 (d, J=6.8 Hz, 1H), 3.71-3.55 (m,2H), 2.41 (s, 3H), 1.39 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 163.96,141.42, 134.94, 131.27, 130.72, 127.30, 124.26, 83.12, 60.86, 27.82,18.21; IR: 1728.22, 1458.18, 1388.75, 1369.46, 1296.16, 1161.15,1118.71, 1068.56, 1037.70, 952.84, 837.11, 759.95 cm⁻¹; HRMS (ESI) calcdfor C₁₃H₁₈O₃S m/z [M+H]⁺: 255.1055; found: 255.1062; HPLC analysis:Chiralcel OD-H (Hex/IPA=90/10, 1.0 mL/min, 230 nm, 22° C.), 7.8, 9.4(major) min, 82% ee; [α]_(D) ²²=−158.63 (c 5.05, MeOH).

(S)-tert-butyl 2-((2-methoxyphenyl)sulfinyl)acetate (10h), from 9h

Pale yellow oil; 99% yield; ¹H NMR (400 MHz, CDCl₃) δ 7.81 (dd, J=7.7,1.7 Hz, 1H), 7.50-7.42 (m, 1H), 7.19 (td, J=7.6, 0.8 Hz, 1H), 6.93 (d,J=8.2 Hz, 1H), 3.89 (s, 3H), 3.75 (dd, J=136.5, 13.7 Hz, 2H), 1.41 (s,9H); ¹³C NMR (100 MHz, CDCl₃) δ 164.34, 155.00, 132.37, 130.29, 125.81,121.64, 110.53, 82.80, 58.46, 55.75, 27.92; IR: 1728.22, 1712.79,1585.49, 1477.47, 1392.61, 1276.88, 1161.15, 1122.57, 1072.42, 1041.56,1018.41, 952.84, 902.69, 837.11, 759.95, 663.51 cm⁻¹; HRMS (ESI) calcdfor C₁₃H₁₈O₄S m/z [M+H]⁺: 271.1004; found: 271.1004; HPLC analysis:Chiralcel OD-H (Hex/IPA=90/10, 1.0 mL/min, 230 nm, 22° C.), 11.3, 12.7(major) min, 89% ee; [α]_(D) ²²=−303.09 (c 5.28, MeOH).

(S)-tert-butyl 2-((2-chlorophenyl)sulfinyl)acetate (10i), from 9i

Yellow oil; 99% yield; ¹H NMR (400 MHz, CDCl₃) δ 7.94 (dd, J=7.8, 1.4Hz, 1H), 7.53 (td, J=7.7, 1.2 Hz, 1H), 7.46 (td, J=7.6, 1.6 Hz, 1H),7.40 (dd, J=7.8, 1.0 Hz, 1H), 3.76 (dd, J=140.3, 13.9 Hz, 2H), 1.43 (s,9H); ¹³C NMR (100 MHz, CDCl₃) δ 163.74, 140.95, 132.32, 130.03, 129.73,127.98, 126.47, 83.32, 59.22, 27.91; IR: 1728.22, 1712.79, 1573.91,1454.33, 1392.61, 1369.46, 1288.45, 1161.15, 1126.43, 1068.56, 1029.99,952.84, 898.83, 837.11, 759.95, 729.09, 663.51 cm⁻¹; HRMS (ESI) calcdfor C₁₂H₁₅ClO₃S m/z [M+H]⁺: 275.0509; found: 275.0507; HPLC analysis:Chiralcel OD-H (Hex/IPA=90/10, 1.0 mL/min, 230 nm, 22° C.), 7.6, 8.9(major) min, 81% ee; [α]_(D) ²²=−238.00 (c 5.41, MeOH).

(S)-tert-butyl 2-(naphthalen-1-ylsulfinyl)acetate (10j), from 9j

Pale yellow solid; 97% yield; mp: 95.6-96.3° C.; ¹H NMR (400 MHz, CDCl₃)δ 8.18 (dd, J=7.3, 1.0 Hz, 1H), 8.01 (dd, J=12.1, 5.1 Hz, 2H), 7.94 (dd,J=6.9, 2.6 Hz, 1H), 7.72-7.63 (m, 1H), 7.63-7.53 (m, 2H), 3.78 (dd,J=58.6, 13.8 Hz, 2H), 1.37 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 164.11,138.89, 133.41, 131.72, 129.05, 128.71, 127.50, 126.78, 125.59, 123.51,121.49, 83.20, 61.69, 27.82; IR: 1728.22, 1504.48, 1454.33, 1369.46,1296.16, 1161.15, 1114.86, 1053.13, 952.84, 898.83, 837.11, 802.39,771.53, 736.81, 702.09 cm⁻¹; HRMS (ESI) calcd for C₁₆H₁₈O₃S m/z [M+H]⁺:291.1055; found: 291.1058; HPLC analysis: Chiralcel OD-H (Hex/IPA=90/10,1.0 mL/min, 230 nm, 22° C.), 12.4 (major), 28.9 min, 83% ee; [α]_(D)²²=−280.80 (c 5.60, MeOH).

(S)-tert-butyl 2-(pyridin-2-ylsulfinyl)acetate (10k), from 9k

Pale yellow oil; 99% yield; ¹H NMR (400 MHz, CDCl₃) δ 8.61 (d, J=4.6 Hz,1H), 7.98 (dt, J=26.9, 7.5 Hz, 2H), 7.40 (dd, J=6.6, 5.5 Hz, 1H), 3.88(ddd, J=102.7, 14.0, 1.0 Hz, 2H), 1.41 (s, 9H); ¹³C NMR (100 MHz, CDCl₃)δ 163.82, 163.68, 149.29, 138.18, 124.85, 120.42, 83.13, 59.28, 27.89;IR: 1728.22, 1577.77, 1562.34, 1454.33, 1423.47, 1392.61, 1369.46,1288.45, 1261.45, 1161.15, 1114.86, 1087.85, 1056.99, 1041.56, 991.41,952.84, 902.69, 837.11, 771.53, 617.22 cm⁻¹; HRMS (ESI) calcd forC₁₁H₁₅NO₃S m/z [M+H]⁺: 242.0851; found: 242.0851; HPLC analysis:Chiralcel OD-H (Hex/IPA=90/10, 1.0 mL/min, 254 nm, 22° C.), 10.6, 12.1(major) min, 52% ee; [α]_(D) ²²=−85.44 (c 5.03, MeOH).

(S)-tert-butyl 2-(benzo[d]thiazol-2-ylsulfinyl)acetate (10l), from 91

Pale yellow solid; 79% yield; mp: 77.9-78.8° C.; ¹H NMR (400 MHz, CDCl₃)δ 8.07 (d, J=8.2 Hz, 1H), 8.02 (d, J=7.9 Hz, 1H), 7.58 (t, J=7.6 Hz,1H), 7.51 (t, J=7.6 Hz, 1H), 4.09 (dd, J=43.2, 14.3 Hz, 2H), 1.46 (s,9H); ¹³C NMR (100 MHz, CDCl₃) δ 176.25, 162.99, 153.69, 136.20, 127.04,126.38, 124.08, 122.31, 84.03, 61.60, 27.93; IR: 1728.22, 1458.18,1392.61, 1369.46, 1288.45, 1261.45, 1157.29, 1068.56, 844.82, 759.95,729.09 cm⁻¹; HRMS (ESI) calcd for C₁₃H₁₅NO₃S₂ m/z [M+H]⁺: 298.0572;found: 298.0572; HPLC analysis: Chiralcel OB-H (Hex/IPA=90/10, 1.0mL/min, 254 nm, 22° C.), 12.5 (major), 14.9 min, 74% ee; [α]_(D)²=−42.92 (c 4.72, MeOH).

Example 12: Sulfoxidation of Other Substrates Using Molybdate System

To further explore the generality of the current catalytic system,substrates containing various functionalities such as amide, nitrile,acrylate, ketone, nitro, phenol and aldehyde were examined (Scheme 5).3-thio acetate substrate 11a can be efficiently oxidized to 3-sulfinylacetate 12a in 88% yield with an excellent enantioselectivity of 94%,while only moderate enantioselectivity of 82% was achieved by directoxidation of 2-sulfinyl amide 11b to modafinil 12b under present system.Interestingly, the substrate bearing electron-deficient alkenes wascompatible with current conditions to afford the sulfide oxidationproduct 12d in good enantioselectivity without any epoxide formation.Moreover, it was noted that benzylic 2-thio ketone substrates weresmoothly converted to their corresponding sulfoxides 12e and 12f in highyield with excellent enantioselectivity. Oxidant- or acid-sensitivefunctional groups in substrates 11g and 11h were typically not affected,providing the hydroxyl and formyl sulfoxides 12g and 12h, respectively,in fairly good yield with moderate enantioselectivity.

The following sulfoxide products are made from their reduced forms(11a-11h) via General Procedure 3, unless otherwise stated.

The absolute configuration of products 12 was assigned by analogy toeither 8f or 10f (Scheme 5).

Characterization of Sulfoxide Products

(S)-methyl 3-(benzhydrylsulfinyl)propanoate (12a), from 11a

White solid; 88% yield; mp: 98.7-99.6° C.; ¹H NMR (400 MHz, CDCl₃) δ7.52-7.46 (m, 2H), 7.46-7.28 (m, 8H), 4.88 (s, 1H), 3.67 (s, 3H),2.94-2.61 (m, 4H); ¹³C NMR (100 MHz, CDCl₃) δ 171.68, 135.35, 134.74,129.27, 129.20, 128.74, 128.52, 128.42, 128.32, 72.78, 52.03, 45.43,26.89; IR: 1732.08, 1492.90, 1361.74, 1238.30, 1176.58, 1045.42, 736.81,702.09 cm⁻¹; HRMS (ESI) calcd for C₁₇H₁₈O₃S m/z [M+H]⁺: 303.1055; found:303.1046; HPLC analysis: Chiralcel AD-H (Hex/IPA=80/20, 1.0 mL/min, 230nm, 22° C.), 14.5 (major), 24.6 min, 94% ee; [α]_(D) ²²=+11.16 (c 5.25,MeOH).

(S)-2-(benzhydrylsulfinyl)acetamide (12b), from 11b

White solid; 96% yield; mp: 160.4-161.2° C.; ¹H NMR (400 MHz, DMSO) δ7.67 (s, 1H), 7.56-7.47 (m, 4H), 7.46-7.38 (m, 4H), 7.38-7.33 (m, 2H),7.30 (s, 1H), 5.33 (s, 1H), 3.29 (dd, J=57.5, 13.6 Hz, 2H); ¹³C NMR (100MHz, DMSO) δ 166.87, 137.68, 135.42, 130.21, 129.54, 128.99, 128.46,128.44, 69.30, 56.64; IR: 3170.97, 1693.50, 1612.49, 1454.33, 1400.32,1033.85, 740.67, 482.20. 455.20 cm⁻¹; HRMS (ESI) calcd for C₁₅H₁₅NO₂Sm/z [M+H]⁺: 274.0902; found: 274.0905; HPLC analysis: Chiralcel AS-H(Hex/IPA=50/50, 1.0 mL/min, 230 nm, 22° C.), 12.8 (major), 29.8 min, 82%ee; [α]_(D) ²²=+14.44 (c 5.24, MeOH).

(R)-2-(benzylsulfinyl)acetonitrile (12c), from 11c

White solid; 87% yield; mp: 110.4-111.8° C.; ¹H NMR (400 MHz, CDCl₃) δ7.47-7.39 (m, 3H), 7.36 (dt, J=4.9, 4.0 Hz, 2H), 4.36-4.18 (m, 2H), 3.42(dd, J=76.6, 16.1 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 130.04, 129.42,129.26, 127.53, 111.27, 57.86, 36.87; IR: 2306.86, 1419.61, 1076.28,894.97, 740.67, 702.09 cm⁻¹; HRMS (ESI) calcd for C₉H₉NOS m/z [M+H⁻]⁺:180.0483; found: 180.0484; HPLC analysis: Chiralcel OB-H (Hex/IPA=90/10,1.0 mL/min, 230 nm, 22° C.), 14.0 (major), 18.2 min, 80% ee; [α]_(D)²²=+58.46 (c 3.05, MeOH).

(S,E)-ethyl 4-(benzylsulfinyl)but-2-enoate (12d), from 11d

Pale yellow oil; 84% yield; ¹H NMR (400 MHz, CDCl₃) δ 7.42-7.31 (m, 3H),7.28 (dd, J=7.6, 1.7 Hz, 2H), 6.93 (dt, J=15.6, 7.8 Hz, 1H), 6.06 (dt,J=15.6, 1.1 Hz, 1H), 4.33-4.08 (m, 2H), 4.06-3.87 (m, 2H), 3.42 (dddd,J=60.4, 13.2, 7.8, 1.2 Hz, 2H), 1.28 (t, J=7.1 Hz, 3H); ¹³C NMR (100MHz, CDCl₃) δ 164.98, 134.61, 129.93, 129.28, 129.05, 128.68, 128.55,60.71, 57.35, 52.26, 14.10; IR: 3032.10, 1712.79, 1651.07, 1496.76,1454.33, 1396.46, 1369.46, 1319.31, 1273.02, 1199.72, 1149.57, 1041.56,979.84, 767.67, 702.09 cm⁻¹; HRMS (ESI) calcd for C₁₃H₁₆O₃S m/z [M+H]⁺:253.0898; found: 253.0896; HPLC analysis: Chiralcel OB-H (Hex/IPA=50/50,1.0 mL/min, 230 nm, 22° C.), 8.5 (major), 18.9 min, 77% ee; [α]_(D)²²=−6.73 (c 4.19, MeOH).

(R)-2-(benzylsulfinyl)-1-(p-tolyl)ethanone (12e), from 11e

Yellow solid; 99% yield; mp: 104.8-106.1° C.; ¹H NMR (400 MHz, CDCl₃) δ7.80 (d, J=8.3 Hz, 2H), 7.42-7.30 (m, 5H), 7.30-7.22 (m, 2H), 4.17 (ddd,J=19.0, 16.5, 8.3 Hz, 4H), 2.42 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ192.05, 145.48, 133.56, 130.45, 129.57, 129.20, 128.86, 128.78, 128.51,57.71, 57.61, 21.72; IR: 1670.35, 1604.77, 1492.90, 1454.33, 1411.89,1315.45, 1280.73, 1184.29, 1072.42, 1029.99, 975.98, 840.96, 763.81,702.09 cm⁻¹; HRMS (ESI) calcd for C₁₆H₁₆O₂S m/z [M+H]⁺: 272.0949; found:272.0944; HPLC analysis: Chiralcel AD-H (Hex/IPA=90/10, 1.0 mL/min, 230nm, 22° C.), 20.0 (major), 30.1 min, 90% ee; [α]_(D) ²²=+37.79 (c 5.48,MeOH).

(R)-2-(benzylsulfinyl)-1-(4-nitrophenyl)ethanone (12f), from 11f

white solid; 95% yield; mp: 153.3-154.1° C.; ¹H NMR (400 MHz, CDCl₃) δ8.31 (d, J=8.8 Hz, 2H), 8.07 (d, J=8.8 Hz, 2H), 7.44-7.29 (m, 5H), 4.20(ddd, J=25.7, 20.3, 10.1 Hz, 4H); ¹³C NMR (100 MHz, CDCl₃) δ 191.50,150.79, 140.48, 130.37, 129.92, 129.10, 128.83, 128.80, 123.98, 57.93,57.31; IR: 1685.79, 1604.77, 1531.48, 1419.61, 1346.31, 1053.13, 894.97cm⁻¹; HRMS (ESI) calcd for C₁₅H₁₃NO₄S m/z [M+H]⁺: 304.0644; found:304.0638; HPLC analysis: Chiralcel AD-H (Hex/IPA=70/30, 1.0 mL/min, 230nm, 22° C.), 20.8 (major), 27.7 min, 85% ee; [α]_(D) ²²=−44.80 (c 1.66,CHCl₃).

(S)-tert-butyl 2-((4-hydroxyphenyl)sulfinyl)acetate (12g), from 11g

White solid; 88% yield; mp: 133.9-135.4° C.; ¹H NMR (400 MHz, CDCl₃) δ7.53 (d, J=8.5 Hz, 2H), 6.96 (d, J=8.5 Hz, 2H), 3.76 (dd, J=117.7, 13.8Hz, 2H), 1.37 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 163.63, 160.90,130.99, 127.00, 116.74, 83.60, 61.97, 27.83; IR: 3055.24, 1724.36,1496.76, 1419.61, 1157.29, 1018.41, 894.97, 740.67 cm⁻¹; HRMS (ESI)calcd for C₁₂H₁₆O₄S m/z [M+H]⁺: 257.0848; found: 257.0862; HPLCanalysis: Chiralcel AS-H (Hex/IPA=80/20, 1.0 mL/min, 230 nm, 22° C.),25.4 (major), 38.3 min, 61% ee; [α]_(D) ²²=−58.27 (c 4.52, MeOH).

(S)-4-(methylsulfinyl)benzaldehyde (12h), from 11h

White solid; 82% yield; mp: 70.2-72.0° C.; ¹H NMR (400 MHz, CDCl₃) δ10.06 (s, 1H), 8.02 (d, J=8.4 Hz, 2H), 7.79 (d, J=8.2 Hz, 2H), 2.75 (s,3H); ¹³C NMR (100 MHz, CDCl₃) δ 191.04, 152.34, 138.06, 130.32, 124.09,43.67; IR: 2850.79, 2738.92, 1701.22, 1593.20, 1573.91, 1415.75,1384.89, 1296.16, 1273.02, 1199.72, 1168.86, 1149.57, 1087.85, 956.69,825.53, 736.81, 694.37 cm⁻¹; HRMS (ESI) calcd for C₈H₈O₂S m/z[M+H]⁺:169.0323; found: 169.0326; HPLC analysis: Chiralcel AS-H(Hex/IPA=70/30, 1.0 mL/min, 230 nm, 22° C.), 31.9, 50.4 (major) min, 65%ee; [α]_(D) ²²=−70.0 (c 2.76, MeOH).

Example 13: Gram-Scale Synthesis of Armodafinil

The practical utility of present catalysis system was furtherdemonstrated by a gram-scale synthesis of psychostimulant drugArmodafinil (FIG. 17). This system uses the bisguanidinium 1b with(R,R)-configuration, which is a stereoisomer of (S,S)-1a that wasreferred to in the earlier examples. The oxidation of MDMMA 7a with alow loading of 0.25 mol % of (R,R)-1b was performed at room temperaturefor 8 h. Following by treatment with ammonia in methanol,(R)-Armodafinil 13 was obtained in 95% yield with an enantioselectivityof 91%.

Synthesis of Armodafinil 13:

A 10 mL round-bottomed flask was charged with a solution of methyl2-(benzhydrylthio)acetate 7a (1.36 g, 5 mmol, 1.0 equiv.) andbis-guanidinium phase-transfer catalyst (R,R)-1b (17.6 mg, 0.0125 mmol,0.0025 equiv.) in ^(n)Bu₂O (100 mL). Then Na₂MoO₄.2H₂O (30 mg, 0.125mmol, 0.025 equiv.), KHSO₄ (340 mg, 2.5 mmol, 0.5 equiv.) and H₂O₂(35%,430 μL, 5 mmol, 1.0 equiv.) were added at room temperature. Theresulting mixture was stirred vigorously and monitored by TLC and 7a wascompletely consumed within 8 h. Purification by running flashchromatography on a short silica gel column using CH₂Cl₂: EtOAc 2:1 asthe eluent afforded the sulfoxide product with (R,R)-configuration, 1.32g, 91% yield, 91% ee. Then the obtained sulfoxide (1.32 g, 4.58 mmol)was treated with 2M ammonical methanol (23 mL, 10.0 equiv.) and theresulting solution was stirred at room temperature for 24 h.Purification by running flash chromatography on a short silica gelcolumn using CH₂Cl₂:MeOH 20:1 as the eluent afforded(R)-2-(benzhydrylsulfinyl)acetamide (13) as a white solid, 1.19 g, 95%yield.

(R)-2-(benzhydrylsulfinyl)acetamide (13)

HPLC analysis: Chiralcel AS-H (Hex/IPA=50/50, 1.0 mL/min, 230 nm, 22°C.), 12.7, 28.8 (major) min, 91% ee; [α]_(D) ²²=−16.25 (c 2.0, MeOH).

A single-crystal structure of (R)-13 is provided in FIG. 10C. Crystaldata for (R)-13: [C₁₅H₁₅NO₂S], M=273.34, monoclinic, P 1 21 1,a=5.6324(3), b=26.1594(16), c=9.3139(5) Å, α=90, β=105.6796(19)°, γ=90°,V=1321.25(13) Å³, Z=4, ρ_(calcd)=1.374 g/cm³, μ(CuKα)=0.242 mm⁻¹,T=103(2) K, Wavelength=0.71073 Å, colorless block. Bruker X8 CCD X-raydiffractionmeter; 8391 independent measured reflections, F² refinement,R₁(obs)=0.0446, wR₂(all)=0.0968, 7453 independent observedabsorption-corrected reflections, 343 parameters. Crystallographic datafor this paper have been deposited at the Cambridge CrystallographicData Centre under deposition number CCDC 1456987.

Example 14: Mechanistic Insights of Molybdate System

TABLE 5

Entry Cat Additive Time (min) Yield (%)^(b) ee (%)^(c)  1 (R,R)-1b —1440  15 −5  2 (R,R)-1b KHSO₄  30 94 −92  3 (R,R)-1b TBAHSO₄  60 89 −89 4 (R,R)-1b CH₃SO₃H 120 84 −5  5 (R,R)-1b CF₃SO₃H  60 98 0   6^(d)(R,R)-1b H₃PO₄ 240 89 −17   7^(d) (R,R)-1b H₂SO₄  10 99 −95   8^(d)(R,R)-1b HCl 240 17 −2   9^(d) (R,R)-1b H₂SO₄ (0.1 equiv.)  10 99 −90 10^(d) (R,R)-1b H₂SO₄ (0.05 equiv.)  90 80 −91  11^(d) (R,R)-1b H₂SO₄(0.01 equiv.) 1440  27 −2   12^(d,e) (R,R)-1b H₂SO₄ 240  0 NA  13^(e)(R,R)-1c —  30 95 −91   14^(e,f) (R,R)-1c —  30 97 −80 Unless otherwiseindicated, reaction was performed with 0.05 mmol of 7a in the presenceof 1 mol % of chiral bisguanidinium (R,R)-1b or (R,R)-1c and 2.5 mol %of Na₂MoO₄•2H₂O in 1.0 mL of ^(i)Pr₂O at room temperature. ^(b)Yield ofthe isolated product. ^(c)Determined by HPLC analysis. ^(d)AqueousH₃PO₄, H₂SO₄, HCl were freshly prepared with concentration of 1.0 M.^(e)Without Na₂MoO₄•2H₂O. ^(f)1.0 equivalent of (R,R)-1c was used in theabsence of aqueous hydrogen peroxide co-oxidant. (R,R)-1c was obtainedby an experiment under similar oxidative condition but without theaddition of substrate MDMMA 7a (see Synthetic Protocol of IsolatedComplex (R,R)-1c, FIG. 14) using bisguanidinium (R,R)-1b. TBA =tetrabutylammonium.

To understand how the catalytic system works, control experiments werealso carried out based on General Procedure 3, unless otherwise stated(Table 5). In the comparison of entries 2 and 3, with 0.5 equivalent oftetrabutylammonium bisulfate (TBAHSO₄) as the additive and only 1 mol %of chiral bisguanidinium (R,R)-1b, the reaction still provided a highdegree of stereocontrol (89% vs 92%) but at a relatively slow rate. Thisindicated that the chiral bisguanidinium dication is much more efficientto activate or interact with the real anionic intermediates thantetrabutylammonium cation. Additionally, several organic sulfonic acids(Table 5, entries 4 and 5) and inorganic acids (Table 5, entries 6-8)were examined as additives. Indeed, except hydrochloric acid, they didaccelerate the oxidation beyond the background reaction (Table 5, entry1). However, the use of sulfuric acid as additive surprisingly achievedhigh enantioselectivity (Table 5, entry 7). Further decreases of theamount of aqueous H₂SO₄ to 5 mol % led to longer reaction time withoutaffecting the enantioselectivity (Table 5, entries 9 and 10) but theloss of enantioselectivity and reactivity were observed with only 1 mol% of aqueous H₂SO₄ (Table 5, entry 11) (Chengxia Miao et al. J. Am.Chem. Soc. 138, 936-943 (2016)). Moreover, sulfuric acid itself cannotact as an activator towards hydrogen peroxide in the absence ofmolybdate salt (Table 5, entry 13). These results suggest that bothmolybdate and sulfate are included in the real active oxidant species(Fabian Taube, et al., J. Chem. Soc., Dalton Trans., 1002-1008 (2002)).

More importantly, previously prepared (R,R)-1c was applied in theoxidative reaction without the addition of any additive or molybdatespecies. Consistent performance in the sulfoxidation of MDMMA 7a byusing 1 mol % of (R,R)-1c was observed (Table 5, entry 14). Suchobservation clearly indicated (R,R)-1c is the catalytically activespecies and an efficient ion-pairing catalyst for enantiodiscrimination.Furthermore, upon treatment of substrate 7a with stoichiometricequivalent of (R,R)-1c in the absence of hydrogen peroxide terminalco-oxidant, oxidative product 8a was achieved in high yield and goodenantioselectivity (Table 5, entry 14). These direct evidences stronglyindicated that (R,R)-1c is the true oxidizing species involving peroxomoiety—which is further explored below in the subsequent examples.

Example 15: Structural Analysis of (R,R)-1c

X-Ray Single Crystal Diffraction

A suitable crystal of (R,R)-1c for X-ray single crystal diffraction wasobtained and the structure of (R,R)-1c was successfully resolved, withbisguanidinium dication and oxodiperoxomolybdosulfate dianion as twocomponents for this ion-pair complex (FIG. 8). According to the X-raydata, it can be found that the achiral anionic metallic species locatesat one side of chiral dicationic counterpart backbone with approachingto the centric bisguanidinium moiety. Moreover, the coordination mode ofanionic part was clearly elucidated (FIG. 8).

This dinuclear oxodiperoxomolybdosulfate moiety has a symmetriccondensate structure comprising one bridging peroxo ligand, one side-onperoxo group and a terminal oxo ligand on each Mo center, and onesulfate group as a bipodal ligand to the two Mo atoms (Laurent Salles,et al., Bull. Soc. Chim. Fr. 133, 319-328 (1996)). Thus each Mo atom is7-coordinated by oxygen atoms in a pentagonal bipyramidal arrangement(Laurent Salles et al. Polyhedron 26, 4786-4792 (2007)). The twoassociated pentagonal bipyramids share one edge [O₉ . . . O₁₀] on thenon-basal plane and the two Mo atoms are connected by two μ-η¹:η²-peroxobridges [O₈-O₉ and O₁₁—O₁₀]. Both Mo₁—O₅ and Mo₂—O₁₂ bonds have the samelength (1.659(7)) Å) which falls into a typical range for Mo═O bond.Generally, bridging peroxo O₈-O₉ (1.482(9) Å) and O₁₀-O₁₁ (1.473(10) Å)bond lengths are slightly longer than the side-on peroxo O₆-O₇(1.458(10) Å) and O₁₃-O₁₄ (1.467(10) Å) bond lengths. Moreover, the twoside-on peroxo groups seem to be the active oxygen donors, which cantransfer two equivalents of active oxygen atom to the substrate (DylanJ. Thompson, et al., Inorg. Chim. Acta 437, 103-109 (2015)).

⁹⁵Mo NMR

⁹⁵Mo NMR spectral data of this novel bisguanidiniumoxodiperoxomolybdosulfate complex (R,R)-1c in d₇-DMF solvent is reportedfor the first time by using the external reference 2 M Na₂MoO₄.2H₂Osolution in D₂O, assigned to 0 ppm. The resonance occurred at −199.29ppm (FIG. 13B) which is attributed to the region characteristic of theoxodiperoxomolybdate species (Andrew C. Dengel, et. al., J. Chem. Soc.,Dalton Trans., 991-995 (1987); V. Nardello, J, et. al., Inorg. Chem. 34,4950-4957 (1995); Jeena Jyoti Boruah, et. al., Green Chem. 15, 2944-2959(2013); Jeena Jyoti Boruah, et. al., Polyhedron 52, 246-254 (2013)). Theappearance of a single and relatively sharp peak in the ⁹⁵Mo NMRspectrum of (R,R)-1c indicated the presence of a single coordinationenvironment for the oxodiperoxomolybdosulfate species with a highsymmetric coordination mode. In addition, the analogue to (R,R)-1c withdi-tetrabutylammonium (TBA) counter cation was prepared following thereported procedure and the resonance of it also occurred at −199.29 ppm(FIG. 13A) (Laurent Salles, et. al., Bull. Soc. Chim. Fr. 133, 319-328(1996)). However, this di-tetrabutylammonium oxodiperoxomolybdosulfatecomplex has poor performance in the oxidative reaction of sulfide 7a,less than 10% conversion within 2 hours, which indicates the catalyticreactivity of metallic anion is strongly affected by the pattern ofion-pairing.

IR

(R,R)-1c was also characterised by IR technique (see Example 1 and FIG.16). The sharp and strong peaks at 972.12 and 871.82 cm⁻¹ are assignedto (Mo═O) and (0-0) stretching frequencies, respectively. And the peaksat 663.51 and 590.22 cm⁻¹ are characteristic of the asymmetric andsymmetric stretching of (Mo—(O₂)) moieties, respectively (Andrew C.Dengel, et. al., J. Chem. Soc., Dalton Trans., 991-995 (1987)). Thepeaks at 1114.86, 1076.28, 1049.27 cm⁻¹ are tentatively assigned to theSO₄ ²⁻ ligand with a lower symmetry when it coordinates to the Mo atom(Fabian Taube, et. al, J. Chem. Soc., Dalton Trans., 1002-1008 (2002)).

Example 16: Use of (R,R)-1c as the Sole Oxidant

TABLE 6 (R,R)-1c as the sole oxidant.

Time Yield ee Entry Cat x (min) (%)^(b) (%)^(c) 1 (R,R)-1c 100   30 97−80 2 (R,R)-1c 50 120  79^(d) −37 3 (R,R)-1c 25 120  50^(d) −31  4^(e) — 1 120  0 —  5^(f) —  1 120 99  89 Unless otherwise indicated, reactionwas performed with 0.05 mmol of 7a in the presence of chiralbisguanidinium (R,R)-1c in 1.0 mL of ^(i)Pr₂O at room temperature.^(b)Yield of the isolated product. ^(c)Determined by HPLC analysis.^(d)Determined by ¹H NMR analysis. ^(e)Catalyst recycled from reactionin entries 2 and 3 was used with the addition of one equivalent ofaqueous H₂O₂. ^(f)Catalyst recycled from reaction in entries 2 and 3 wasused with the addition of 0.5 equivalent of KHSO₄ and one equivalent ofaqueous H₂O₂.

The effect of varying a stoichiometric amount of (R,R)-1c as the soleoxidant was examined in the asymmetric oxidation of sulfide 7a. In thepresence of one equivalent of (R,R)-1c, the reaction proceeded well toafford the product in 97% yield with a good enantioselectivity of 80%(Table 6, entry 1). However, the lower of its amount to 0.5 equivalentor 0.25 equivalent, a dramatic decrease of enantioselectivity wasobserved. Employing 0.25 equivalent of (R,R)-1c in our current systemled to the formation of 50% sulfoxide (determined by crude ¹H NMR—seeFIG. 13). Without wishing to be bound by theory, this result appears toshow that there is a transfer of two equivalents of active oxygen from(R,R)-1c to substrate 7a.

Without wishing to be bound by theory, the significant deterioration ofenantioselectivity is probably ascribed to insufficient stereocontrol ofthe oxomonoperoxosulfato molybdenum dianion of (R,R)-1c in the transferof second active oxygen. In other words, the second active oxygen of Ashould be out of the catalytic cycle in the presence of terminal oxidanthydrogen peroxide in order to maintain the dimeric structure whichhighly affect the enantiofacial discrimination process before theformation of B. Upon the completion of this stoichiometric reaction, thecatalyst was recovered by running a flash silica column, but thereaction has shown loss of activity of the catalyst in the presence ofH₂O₂, which probably indicates the collapse of the dimeric structure ofthe anionic part (Table 6, entry 4). It was noteworthy that the catalystcan be remarkably regenerated and reactivated by the addition of 0.5equivalent of KHSO₄ in the reaction to afford high enantioselectivityagain (Table 6, entry 5).

Based on the aforementioned experimental results, a plausiblemechanistic pathway was tentatively proposed (see FIG. 12).

The invention claimed is:
 1. A complex of formula (I), comprising anorganic cation (A) and an inorganic anion (B):

wherein: each R₁ independently represents C₁₋₃ alkyl-aryl or C₁₋₃alkyl-Het^(a), which aryl or Het^(a) groups are unsubstituted or aresubstituted by from one to five R₃ substituents; each R₂ independentlyrepresents aryl, which group is unsubstituted or substituted by from oneto five R₄ substituents; Het^(a) represents a 4- to 14-memberedheterocyclic group containing one or more heteroatoms selected from O, Sand N, which heterocyclic group comprises one, two or three rings; eachR₃ and R₄ independently represents halo, branched or unbranched C₁₋₆alkyl, branched or unbranched C₂₋₆ alkenyl, branched or unbranched C₂₋₆alkynyl; C₃₋₆ cycloalkyl, aryl or OR₅; R₅ represents H, branched orunbranched C₁₋₆ alkyl, branched or unbranched C₂₋₆ alkenyl, branched orunbranched C₂₋₆ alkynyl, C₃₋₆ cycloalkyl or aryl, wherein alkyl,alkenyl, alkynyl, cycloalkyl, and aryl, when present in R₃, R₄, and R₅,are optionally substituted by one or more halogen atoms.
 2. The complexof claim 1, wherein: each R₁ independently represents C₁₋₃ alkyl-phenyl,which phenyl group is substituted by from two to four R₃ substituents;each R₂ independently represents phenyl, which group is unsubstituted orsubstituted by from one to two R₄ substituents; each R₃ and R₄independently represents fluoro, branched or unbranched C₁₋₆ alkyl, C₃₋₆cycloalkyl or OR₅; R₅ represents branched or unbranched C₁₋₃ alkyl orC₃₋₆ cycloalkyl, wherein alkyl and cycloalkyl, when present in R₃, R₄,and R₅, are optionally substituted by one or more halogen atoms.
 3. Thecomplex of claim 2, wherein: each R₁ independently representsCH₂-phenyl, which phenyl group is substituted by from two to three R₃substituents; each R₂ independently represents unsubstituted phenyl;each R₃ independently represents fluoro, branched or unbranched C₃₋₅alkyl or OR₅; and R₅ represents branched or unbranched C₁₋₃ alkyloptionally substituted by one or more halogen atoms.
 4. The complex ofclaim 1, wherein the organic cation (A) is enantioenriched.
 5. Thecomplex of claim 1, where the organic cation (A) is selected from: (i)1,4-bis((4S,5S)-1,3-bis(3,5-di-tert-butylbenzyl)-4,5-diphenylimidazolidin-2-ylidene)piperazine-1,4-diium;(ii)1,4-bis((4R,5R)-1,3-bis(3,5-di-tert-butylbenzyl)-4,5-diphenylimidazolidin-2-ylidene)piperazine-1,4-diium;(iii)1,4-bis((4S,5S)-1,3-bis(3,5-di-tert-butyl-4-methoxybenzyl)-4,5-diphenylimidazolidin-2-ylidene)piperazine-1,4-diium;(iv)1,4-bis((4R,5R)-1,3-bis(3,5-di-tert-butyl-4-methoxybenzyl)-4,5-diphenylimidazolidin-2-ylidene)piperazine-1,4-diium;(v)1,4-bis((4S,5S)-1,3-bis(3,5-di-tert-butyl-4-fluorobenzyl)-4,5-diphenylimidazolidin-2-ylidene)piperazine-1,4-diium;and (vi)1,4-bis((4R,5R)-1,3-bis(3,5-di-tert-butyl-4-fluorobenzyl)-4,5-diphenylimidazolidin-2-ylidene)piperazine-1,4-diium.6. The complex of claim 5, where the organic cation (A) is selectedfrom: (i)1,4-bis((4S,5S)-1,3-bis(3,5-di-tert-butylbenzyl)-4,5-diphenylimidazolidin-2-ylidene)piperazine-1,4-diium;and (ii)1,4-bis((4R,5R)-1,3-bis(3,5-di-tert-butylbenzyl)-4,5-diphenylimidazolidin-2-ylidene)piperazine-1,4-diium.7. A process of manufacturing a sulfoxide, comprising reacting acompound of formula (II):

in the presence of a complex of formula (I), as defined in claim 1,wherein in the compound of formula (II): R₆ represents H, branched orunbranched C₁₋₆ alkyl, branched or unbranched C₂₋₆ alkenyl, branched orunbranched C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C(O)R₁₀, C(O)OR₁₁ or OR₁₂,wherein alkyl, alkenyl, alkynyl, and cycloalkyl, when present in R₆, areoptionally substituted by one or more substituents selected from halo,OR₈, and C(O)R₉; R₇ represents CH(R₁₃)(R₁₄), Het^(b) or aryl, whereinHet^(b) and aryl, when present in R₇, are optionally substituted by oneor more substituents selected from halo, NO₂, CN, C(O)R₁₅, OR₁₆, andbranched or unbranched C₁₋₆ alkyl optionally substituted by one or morehalo atoms; R₁₃ and R₁₄ each independently represent H, aryl or Het^(c),provided that at least one of R₁₃ and R₁₄ is not H, wherein aryl andHet^(c), when present in R₁₃ or R₁₄, are optionally substituted by oneor more substituents selected from halo, branched or unbranched C₁₋₆alkyl, C(O)R₁₇ and OR₁₈; R₈, R₁₂, R₁₆ and R₁₈ each independentlyrepresent H, C(O)R₁₉ or a branched or unbranched C₁₋₆ alkyl optionallysubstituted by one or more halo atoms; R₉, R₁₀, R₁₅ and R₁₇ eachindependently represent OR₂₀, N(R_(20′))(R_(20″)) or a branched orunbranched C₁₋₆ alkyl optionally substituted by one or more halo atoms;R₁₁ represents a branched or unbranched C₁₋₆ alkyl optionallysubstituted by one or more halo atoms; R₁₉, R₂₀, R_(20′) and R_(20″)each independently represent H or a branched or unbranched C₁₋₆ alkyloptionally substituted by one or more halo atoms; Het^(b) and Het^(c)represents a 4- to 14-membered heteroaromatic group containing one ormore heteroatoms selected from O, S and N, which heteroaromatic groupcomprises one, two or three rings; and n represents from 1 to
 10. 8. Theprocess of claim 7, wherein in the compound of formula (II): R₆represents branched or unbranched C₁₋₄ alkyl, branched or unbranchedC₂₋₄ alkenyl, C(O)R₁₀, or C(O)OR₁₁, wherein alkyl and alkenyl, whenpresent in R₆, are optionally substituted by one or more substituentsselected from halo and C(O)R₉; R₉ and R₁₀ each independently representOR₂₀ or a branched or unbranched C₁₋₄ alkyl optionally substituted byone or more halo atoms; R₁₁ represents a branched or unbranched C₁₋₄alkyl optionally substituted by one or more halo atoms.
 9. The processof claim 7, wherein in the compound of formula (II): R₇ representsCH(R₁₃)(R₁₄), phenyl or naphthyl, wherein phenyl or naphthyl, whenpresent in R₇, are optionally substituted by one or more substituentsselected from halo, C(O)R₁₅, OR₁₆, and branched or unbranched C₁₋₆ alkyloptionally substituted by one or more halo atoms; R₁₃ and R₁₄ eachindependently represent H, phenyl or naphthyl, provided that at leastone of R₁₃ and R₁₄ is not H, wherein phenyl and naphthyl, when presentin R₁₃ or R₁₄, are optionally substituted by one or more substituentsselected from halo, branched or unbranched C₁₋₃ alkyl, C(O)R₁₇ and OR₁₈.10. The process of claim 7, wherein the process provides anenantiomerically enriched sulfoxide as the product.
 11. The process ofclaim 7, wherein the process further comprises using the complex offormula (I) in a catalytic amount in combination with at least one molarequivalent, relative to the compound of formula (II), of an oxidisingagent.
 12. The process of claim 11, wherein the process provides thecomplex of formula (I) in situ through reaction of an organic cation (A)with a molybdenum-containing salt and a sulfur-containing additivewhere: the organic cation (A) is provided as a salt with a counterionselected from chloride; the molybdenum-containing salt is M₂MoO₄ or(NH₄)₆MoO₂₄ or solvates thereof, where M represents Na, K or Li; and thesulfur-containing additive is selected from one or more of the groupconsisting of NaHSO₄, KHSO₄, H₂SO₄, and tetrabutylammonium bisulfate(TBAHSO₄).